Nationa

Brea

Progre

Addressing 

the Breast Cance
 National Cancer Institute

 Breast Cancer 

 Progress Report 

 Addressing the Recommendations 

 of the Breast Cancer Progress Review Group 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Cancer Institute

October 2004

NCI Breast Cancer Progress Report October 2004

i

Table of Contents

From the Working Group .................................................................................................................. iii

Acknowledgments............................................................................................................................. iv

Executive Summary ........................................................................................................................... 1

Chapter 1: Breast Cancer Research, 1998-2003............................................................................. 1-1

The Breast Cancer Progress Review Group ..................................................................................................... 1-2

Six Years of Progress.......................................................................................................................................... 1-3

This Progress Report........................................................................................................................................ 1-15

Chapter 2: Initiatives........................................................................................................................ 2-1

NCI’s Investment and Response........................................................................................................................ 2-2

Specialized Programs of Research Excellence (SPOREs).............................................................................. 2-14

Chapter 3: Breast Cancer Biology................................................................................................... 3-1

NCI’s Investment and Response........................................................................................................................ 3-1

Ongoing NCI Research: Recent Progress in Breast Cancer Biology............................................................... 3-8

Continuing Needs and Evolution .................................................................................................................... 3-12

NCI-Supported Research Referenced in Chapter 3........................................................................................ 3-12

Chapter 4: Etiology of Breast Cancer............................................................................................. 4-1

NCI’s Investment and Response........................................................................................................................ 4-1

Ongoing NCI Research: Recent Progress in Breast Cancer Etiology.............................................................. 4-8

Continuing Needs and Evolution .................................................................................................................... 4-10

NCI-Supported Research Referenced in Chapter 4........................................................................................ 4-11

Chapter 5: Breast Cancer Prevention ............................................................................................. 5-1

NCI’s Investment and Response........................................................................................................................ 5-1

Ongoing NCI Research: Recent Progress in Breast Cancer Prevention ......................................................... 5-9

Continuing Needs and Evolution .................................................................................................................... 5-11

NCI-Supported Research Referenced in Chapter 5........................................................................................ 5-11

Chapter 6: Early Detection, Diagnosis, and Prognosis of Breast Cancer.................................... 6-1

NCI’s Investment and Response........................................................................................................................ 6-2

Ongoing NCI Research: Recent Progress in Breast Cancer Early Detection, 

Diagnosis, and Prognosis ................................................................................................................................ 6-12

Continuing Needs and Evolution .................................................................................................................... 6-13

NCI-Supported Research Referenced in Chapter 6........................................................................................ 6-13
October 2004 NCI Breast Cancer Progress Report

ii

Chapter 7: Breast Cancer Treatment .............................................................................................. 7-1

NCI’s Investment and Response........................................................................................................................ 7-2

Ongoing NCI Research: Recent Progress in Breast Cancer Treatment ........................................................ 7-12

Continuing Needs and Evolution .................................................................................................................... 7-16

NCI-Supported Research Referenced in Chapter 7........................................................................................ 7-16

Chapter 8: Breast Cancer Control, Survivorship, and Outcomes ................................................ 8-1

NCI’s Investment and Response........................................................................................................................ 8-3

Ongoing NCI Research: Recent Progress in Breast Cancer Control, Survivorship,

and Outcomes................................................................................................................................................... 8-20

Continuing Needs and Evolution .................................................................................................................... 8-22

NCI-Supported Research Referenced in Chapter 8........................................................................................ 8-22

Appendix A: Breast Cancer Working Group Membership Roster

Appendix B: NCI-Supported Research Projects Relevant to Breast Cancer That Were Active 

in 2003

Appendix C: U.S. Patents Resulting From NCI-Funded Research on Breast Cancer, 1998-2003
NCI Breast Cancer Progress Report October 2004

iii

From the Working Group

It is our pleasure to submit the Breast Cancer Progress Report to the Director of the National Cancer Institute (NCI). It 

constitutes the first assessment of progress in addressing the research priorities identified in the 1998 report of the Breast 

Cancer Progress Review Group (PRG) entitled Charting the Course: Priorities for Breast Cancer Research. This progress report 

characterizes trends in the NCI breast cancer research portfolio from 1998 to 2003. It presents trends in measures of progress 

as broad as overall NCI funding levels and as specific as numbers of projects relevant to particular research priorities.

This report is designed to assist the Institute in efforts to accelerate progress against breast cancer by assessing past research 

investments and identifying future research needs. It is a unique reference documenting NCI-supported breast cancer research 

and the resources available to the breast cancer research community. We believe that this report will enable readers to better 

understand the scope of the Institute’s breast cancer research portfolio and identify research and information resources.

Respectfully,

Jeff Abrams, Chair

Margaret Ames

Rachel Ballard-Barbash

Louise Brinton

Rashmi Gopal-Srivastava

Carl Jaffe

Karen Johnson

Anna Levy

Cheryl Marks

Cherie Nichols

Julia Rowland

Lalitha Shankar

Steve Taplin

Sheila Taube

Barbara Vonderhaar

Debbie Winn

JoAnne Zujewski
October 2004 NCI Breast Cancer Progress Report

iv

Acknowledgments

The development of this progress report by the NCI Breast Cancer Working Group would not have been possible without 

significant contributions from many other individuals. We would especially like to recognize the work of the following 

individuals and organizations.

■ Jim Corrigan, Kevin Callahan, and other staff of the NCI Office of Science Planning and Assessment (OSPA) made 

contributions in a variety of areas, including expertise on the PRGs, knowledge of NCI initiatives and programs, 

development of measures of progress, design of the process for mapping NCI-funded projects to PRG priorities, 

participation in working group meetings, and review of draft documents.

■ The following NCI staff provided expertise on the current and recent research activities of the NCI: Barbara Dunn and 

Ronald Lubet of the Division of Cancer Epidemiology and Genetics and Tracy Lugo-Lively of the Division of Cancer 

Treatment and Diagnosis. From the Division of Cancer Control and Population Sciences, Helen Meissner, Gary Kreps, 

Veronica Chollette, Robin Yabroff, Joan Warren, Martin Brown, Joe Lipscomb, and Nancy Breen identified areas of progress 

in their respective programs and the relevance of their grants to the original PRG priorities.

■ Other NCI staff contributed essential data. Brenda Edwards and Lynn Ries of the Surveillance Epidemiology and End 

Results (SEER) program in the Division of Cancer Control and Population Sciences (DCCPS) provided expertise and data 

on trends in disease statistics. Lakshmi Grama of the Office of Cancer Information Products and Systems (CIPS) and Teri 

Brown of the Office of the Deputy Director for Extramural Science contributed expertise and data on clinical trials. Staff 

of the Financial Management Branch (FMB) provided information on breast cancer research funding. Staff in the Division 

of Extramural Activities (DEA), the Center for Cancer Research (CCR), and the Division of Cancer Epidemiology and 

Genetics (DCEG) provided data on extramural and intramural NCI-sponsored research projects.

■ The staff of Science Applications International Corporation (SAIC) contributed significant technical expertise and dedicated 

effort to the management, analysis, technical writing, and production of the report. SAIC’s efforts were led by Jeff Zalatoris 

and Catherine Hall. Significant contributions were made by Deborah Berlyne, Karen Rulli, Sabina Robinson, Anita 

Sabourin, Quentin Scott, Glenn Bell, Joel Glover, Adam Book, Beth Mathews-Bradshaw, and their colleagues.

■ The staff of NOVA Research Company, led by Vicki Butz and Ed Rorie, managed the layout and preparation of the final 

report.

■ The staff of Constella Group, particularly Paul Nedzbala and Jeffrey Morris, assisted in assembling data on the NCI’s breast 

cancer research portfolio.
NCI Breast Cancer Progress Report October 2004

Executive Summary 1

Executive Summary

Breast cancer is the most common non-skin cancer in women and the second most common cause of cancer-related death in 

U.S. women. An estimated 215,000 new breast cancer diagnoses and 40,000 breast cancer deaths are expected in 2004. White 

women have the highest breast cancer incidence rates, followed by African-American women. While overall mortality due to 

breast cancer has been declining during the past decade, the rate for African-American women is greater than that for women 

of other racial/ethnic groups. These recent trends of stabilizing incidence and decreasing mortality rates are encouraging, but 

breast cancer remains a major health burden for American women and requires continued action.

In 1997, the National Cancer Institute (NCI) convened the Breast Cancer Progress Review Group (PRG), a multidisciplinary 

working group of scientists, clinicians, and advocates, to help NCI define a national research agenda for breast cancer. The 

Breast Cancer PRG issued a 1998 report entitled Charting the Course: Priorities for Breast Cancer Research, which included 

research questions that should be addressed to advance prevention, detection, diagnosis, and treatment of breast cancer. An 

internal NCI Breast Cancer Working Group was convened in 2004 to assess the research progress made since the release of this 

report.

The NCI Breast Cancer Progress Report documents trends in the NCI breast cancer research portfolio from 1998 to 2003. 

Multiple measures of progress are presented at varying levels of specificity, ranging from overall trends in NCI funding, 

projects, and resulting peer-reviewed publications to more specific trends in the number of projects relevant to particular 

research priorities identified by the PRG.

Between 1998 and 2003, NCI substantially expanded investments in breast cancer research, as evidenced by:

■ Increasing breast cancer funding by nearly 60%, from $348.6 million in 1998 to $548.7 million in 2003.

■ Increasing the number of relevant projects by 60%.

■ Expanding ongoing and initiating new programs to sustain and advance both basic and clinical breast cancer research.

■ Expanding the Breast Specialized Programs of Research Excellence (SPOREs) network from 4 to 10 sites.

■ Expanding collaborative efforts, public-private partnerships, and shared resources to improve the capacity to conduct breast 

cancer clinical trials.

During these years, new and innovative types of treatment, preventive measures, and diagnostic techniques have been 

developed and approved or are being studied in clinical trials, including:

■ Tamoxifen (Nolvadex®) for the prevention of breast cancer in high-risk women.

■ Aromatase inhibitors (anastrozole, exemestane) for treatment of estrogen receptor-positive breast cancer.

■ Monoclonal antibodies (Herceptin®) for treatment of tumors that express Her2/ErbB2.

■ Sentinel node biopsy for less-invasive surgical diagnosis and prognosis.

■ Lumpectomy with radiation as an equivalent alternative to mastectomy for certain stages of disease.

■ Preoperative (neoadjuvant) therapy to reduce the size of large tumors, thereby allowing more women to undergo breastconserving therapy.

Work is under way to translate the discoveries generated by this expanded investment into new breast cancer prevention, 

detection, diagnosis, and treatment interventions that will save lives. The following two pages summarize NCI’s investment by 

research category.

NCI’s ability to capitalize on advances in breast cancer research and care will require continued basic, translational, and clinical 

research support. This progress report, which documents NCI’s responsiveness to the recommendations of the Breast Cancer 

PRG, will help guide the Institute’s efforts to make course corrections and develop new recommendations regarding breast 

cancer research.
October 2004 NCI Breast Cancer Progress Report

2 Executive Summary

NCI’s Breast Cancer Research Investment

NCI’s breast cancer research investment increased 

from $348.6 million in 1998 to $548.7 million 

in 2003.

Biology

■ Funding increased from $43.2 million to $86 

million.

■ The number of projects increased from 257 to 

504.

■ New initiatives included the Bioengineering 

Nanotechnology Initiative, Complex Formation in 

Hormonal Regulation of Gene Expression, the Mammalian Gene Collection, and Molecular and Cellular Biology of 

Metastatic Tumor Cells.

Etiology

■ Funding increased from $75.3 million to $107.2 million.

■ The number of projects increased from 263 to 424.

■ New initiatives included Breast Cancer and the Environment Research Centers, Cohort Studies in Cancer 

Epidemiology, Interdisciplinary Studies in the Genetic Epidemiology of Cancer, and the NCI Cohort Consortium.

Prevention

■ Funding increased from $28.9 million to $43.7 million.

■ The number of projects increased from 190 to 295.

■ New initiatives included Chemoprevention of Estrogen Receptor-Negative Breast Cancer Preclinical Studies, Phase I 

and II Cancer Prevention Clinical Trials Consortia, the Study of Tamoxifen and Raloxifene (STAR) Trial, and the 

Rapid Access to Preventive Intervention Development Program.

Early Detection, Diagnosis, and Prognosis

■ Funding increased from $36.4 million to $73.2 million.

■ The number of projects increased from 197 to 288.

■ New initiatives included Development of Digital Mammography Displays and Workstations, Development of 

Novel Technologies for In Vivo Imaging, the Diagnostic Imaging Network–American College of Radiology Imaging 

Network, the Early Detection Research Network, and Innovative Technologies for the Molecular Analysis of Cancer.

Treatment

■ Funding increased from $52 million to $108.2 million.

■ The number of projects increased from 302 to 493.

■ New initiatives included Cancer Therapy-Related Use of Genetically Engineered Mice, Development and Application 

of Imaging in Therapeutic Studies, Quick Trials for Novel Cancer Therapies, and the Translational Research Initiative.

Growth of NCI’s Investment in Extramural Research 

by Scientific Category

0 20 40 60 80 100 120

Cancer Control, Survivorship, and Outcomes

Treatment

Early Detection, Diagnosis, and Prognosis

Prevention

Etiology

Biology

Millions of Dollars

1998

2003
NCI Breast Cancer Progress Report October 2004

Executive Summary 3

Cancer Control, Survivorship, and Outcomes

■ Funding increased from $46.6 million to $82.8 million.

■ The number of projects increased from 224 to 274.

■ New initiatives included Cancer Control PLANET, Centers of Excellence in Cancer Communications Research, 

Exploratory Grants for Behavioral Research in Cancer Control, Health Communications in Cancer Control, and 

Minority and Underserved Cancer Survivors.

Examples of Progress Resulting from 

NCI’s Breast Cancer Research Investment

Biology

■ Recent advances include new mouse models 

that mimic breast cancer in humans, the 

discovery of factors that contribute to 

mammary tumorigenesis, and elucidation of the 

functional characteristics of mammary epithelial 

stem cells.

■ Future investment is needed in the areas of 

normal mammary development and the integration of 

biological information across various model systems.

Etiology

■ Recent advances include the identification of new breast cancer susceptibility genes, determining environmental 

influences on breast cancer development, and identifying behavioral risk factors.

■ Future investment is needed in validating the association and causation of putative susceptibility genes with breast 

cancer risk, identifying linkages between genes and the environment, and understanding the role of endogenous 

hormones.

Prevention

■ Recent advances include the development of new models of precancerous biology, determining the association between 

the consumption of certain dietary components and reduced breast cancer risk, and identifying effective strategies for 

reducing breast cancer incidence.

■ Future investment is needed in developing an intervention strategy that reduces the incidence of both ER-positive and 

ER-negative breast cancer and determining why some of the women who use preventive interventions like tamoxifen 

develop breast cancer in spite of the intervention. 

Early Detection, Diagnosis, and Prognosis

■ Recent advances include the development of novel digital imaging devices, newly identified biologic markers, and the 

use of computers to improve the diagnostic accuracy of breast imaging.

■ Future investment is needed in improving the sensitivity and specificity of screening film mammography and the 

reproducibility of computer-aided devices and determining the uses of newly identified biomarkers.

Growth of NCI’s Breast Cancer Research Program 

by Scientific Category

Cancer Control, Survivorship, and Outcomes

Treatment

Early Detection, Diagnosis, and Prognosis

Prevention

Etiology

Biology

1998

2003

0 100 200 300 400 500 600

Number of Research Projects
October 2004 NCI Breast Cancer Progress Report

4 Executive Summary

Treatment

■ Recent advances include improved treatment of in situ disease, refinements in all aspects of the traditional treatment 

paradigm, and treatments that prolong survival in women with nonoperable breast cancer while maintaining quality of 

life.

■ Future investment is needed in the development of noninvasive approaches for primary breast cancer ablation and 

integrating noninvasive imaging techniques to better appreciate the activity and mechanism of action of targeted 

therapies in Phase I and II studies.

Cancer Control, Survivorship, and Outcomes

■ Recent advances include techniques to increase the number of women screened for breast cancer, examining the 

impact of breast density and breast positioning on mammographic accuracy, and understanding the impact of social 

support on survivors’ well-being.

■ Future investment is needed in communications strategies to educate more women about the importance of 

mammography, increasing the rate at which underserved populations are screened for breast cancer, and ways to 

increase the accuracy with which mammograms are interpreted.
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-1

Chapter 1:

Breast Cancer Research, 1998-2003

By applying and expanding our foundation of knowledge, and with ample measures of teamwork, 

technology, and tenacity, major progress against breast cancer can and will be made in the next 5 to 10 

years. Charting the Course: Priorities for Breast Cancer Research

Breast cancer is the most common non-skin cancer in women and the second most common cause of cancer-related death in 

U.S. women.1 An estimated 215,000 new breast cancer diagnoses and 40,000 breast cancer deaths are expected in 2004.2

As shown in Figure 1-1, breast cancer incidence rates increased steadily between 1973 and the late 1990s, following the 

increased use of mammography.3 After peaking in 1998, incidence has declined slightly. White women have a higher incidence 

of breast cancer than any other race, and African-American women have the second highest incidence rates. Incidence rates for 

whites and African Americans have increased similarly over the past three decades.

Overall mortality rates were stable between 1973 and the early 1990s,4 and then began a steady decline that has continued 

throughout the last decade (Figure 1-2, page 2). In 2001, mortality rates were lower than at any time since 1973, when SEER 

began collecting these data. The most recent mortality rates represent an impressive decrease of approximately 20% from the 

rates in the 1980s. However, while mortality rates in white women were stable until the early 1990s and then began declining, 

mortality rates for African-American women increased steadily through the 1980s, surpassing the rates for white women and all 

races combined in that decade. Mortality rates for African-American women began to decline in the mid-1990s, although they 

are still about 35% higher than rates for white women.

1 NCI’s Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, 1975-2001.

2 See Note 1.

3 The first year in which incidence and mortality data were collected by the NCI’s SEER program for all races, whites, and blacks, was 1973. Beginning in 1992, the data 

collected were expanded to include additional racial/ethnic groups. The most recent year for which analyzed SEER data are available is 2001.

4 See Note 1.

Asian or Pacific Islander

Hispanic

Whites

African Americans

All Races

0

20

40

60

80

100

120

140

160

1973 1977 1981 1985 1989 1993 1997 2001

American Indian, Aleutian

Islander, or Eskimo

Figure 1-1. Breast cancer incidence in the United States

Data derived from NCI’s SEER Program
October 2004 NCI Breast Cancer Progress Report

1-2 Chapter 1: Breast Cancer Research, 1998-2003

Breast cancer is associated with a large economic toll in addition to premature death, disability, and treatment sequelae, 

including quality-of-life issues. It is estimated that $5.4 billion is spent in the United States each year on treatment of the 

disease.5 Lost productivity and wages are additional burdens.

The Breast Cancer Progress Review Group

In September 1997, the National Cancer Institute (NCI) convened a multidisciplinary committee of scientists, clinicians, and 

advocates to review the field of breast cancer research and make prioritized recommendations concerning the most needed 

and promising directions for future NCI investment. In August 1998, this Breast Cancer Progress Review Group (PRG) 

issued its report Charting the Course: Priorities for Breast Cancer Research, which addressed eight categories of breast cancer 

research: Biology; Etiology; Genetics; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment; Cancer Control; and 

Outcomes. For each research category, the report included a synopsis of current knowledge, a discussion of identified goals, 

barriers to progress, and key scientific questions and opportunities, accompanied by recommended actions.6

The Breast Cancer PRG was one of two PRGs formed in 1997. The Breast Cancer PRG was composed of 30 nationally 

prominent members from academia, industry, nonprofit organizations, and government, with complementary backgrounds in 

basic, translational, and clinical research and in breast cancer advocacy issues. The objectives of the Breast Cancer PRG were 

to review the state of the science, assess the existing NCI breast cancer research portfolio, identify and prioritize key scientific 

questions, and develop recommendations for action. The expertise of the PRG members was complemented by 200 additional 

scientists, clinicians, and advocates who participated in a roundtable meeting.

Since the Breast Cancer PRG issued its report, the NCI has increased its investment in research relevant to breast cancer 

in terms of dollars spent and the number of projects supported. Numerous resources and programs have been sustained, 

expanded, and/or developed. During this time, the NCI has improved the monitoring of basic and clinical research to better 

track progress and plan future goals. The Institute has also enhanced early detection methods, developed novel treatments, 

identified new prevention mechanisms, and improved our understanding of genetic predisposition. Ultimately, these 

accomplishments have helped reduce mortality from breast cancer.

0

5

10

15

20

25

30

35

40

45

50

1973 1977 1981 1985 1989 1993 1997 2001

Deaths per 100,000 Women

Hispanic

Asian or Pacific Islander

Whites

African American

All Races

American Indian, Aleutian

Islander, or Eskimo

Figure 1-2. Breast cancer mortality in the United States

5 In 1996 dollars, as determined by Brown, Riley, and Etzioni and reported in the NCI’s Cancer Progress Report—2003 Update.

6 The Breast Cancer PRG report identified 64 investigative priorities; three of these priorities were further divided into 28 subpriorities. Accompanying the 64 investigative 

priorities were 163 recommended actions. Although the PRG report included 64 investigative priorities, some had overlapping content. For reporting purposes, the NCI 

has combined selected priorities’ overlapping content, as described in the appropriate chapters.
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-3

Peer-reviewed publications resulting from NCI-sponsored efforts show that much progress has been made in specific topic areas 

identified as promising by the PRG. Further demonstration of progress can be found in breast cancer-related patents that have 

been issued and changes in clinical practice that have been adopted.

In 2004, the NCI established an internal Breast Cancer Working Group to assist in planning, monitoring, and tracking 

progress in addressing the recommendations of the Breast Cancer PRG. This report includes the Breast Cancer Working 

Group’s findings regarding the NCI’s responsiveness to the PRG recommendations during the years 1998 through 2003.

Six Years of Progress

In the years that followed the release of the Breast Cancer PRG report, the number of investigator-initiated research projects 

relevant to breast cancer increased, and specific research initiatives were implemented or expanded. In the sections that follow, 

an overview is provided for the following:

■ The NCI’s investment in breast cancer research, in terms of dollars invested; research projects supported; clinical trials 

supported; initiatives undertaken; and resources developed, maintained, and expanded.

■ The return on NCI’s investment in terms of research results obtained and applied.

Investment in Breast Cancer Research

Dollars Invested

NCI’s commitment to addressing the identified challenges and opportunities in breast cancer research is demonstrated by 

growing investments in relevant activities. Figure 1-3 shows dollar estimates for NCI breast cancer spending from fiscal year 

(FY) 1998 through FY2003. Over the 6 year period, NCI’s overall breast cancer investment increased by almost 60%. For each 

of these years, NCI’s support for breast cancer research was greater than that for any other cancer site.

Values include NCI’s total intramural and extramural 

support for breast cancer research as reported by the 

Financial Management Branch of the NCI’s Office of 

Budget and Financial Management (NCI FactBook).

The majority of funds devoted to breast cancer research 

supported the extramural research program. Figure 1-4 

(page 4) shows the NCI’s dollar investment for breast 

cancer-relevant research during FY1998-2003. This 

information is broken down according to the Common 

Scientific Outline (CSO), a classification system created 

to provide a common approach to comparing and 

assessing cancer research that is supported by different 

funding organizations.7

To derive the values for extramural research, dollars associated with each funded project were first prorated by estimated breast 

cancer relevance, and this portion was then equally distributed among applicable CSO research categories. Dollars directed at 

resources are included in the values for the research categories.

Figure 1-3. Estimate of total NCI dollars for breast cancerrelevant research

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars

7 Although the seven categories of the CSO are similar to the eight categories of the Breast Cancer PRG, notable differences include the CSO’s category of scientific model 

systems; the combined category of cancer control, survivorship, and outcomes; and the inclusion of genetics in the other categories. The CSO is described in its entirety at 

http://researchportfolio.cancer.gov/cso.html. 
October 2004 

1-4 Chapter 1: Breast Cancer Research, 1998-2003

NCI Breast Cancer Progress Report 

Research Projects Supported

Between 1998 and 2003, the number of NCIsponsored research projects relevant to breast 

cancer increased by 60%. Figure 1-5 shows the 

number of projects with breast cancer relevance8

(i.e., 25% or greater) that were funded by the 

NCI each year during FY1998-2003. Numbers 

of funded breast cancer projects within each 

research category are shown in Figure 1-6 (page 

5). Details concerning the NCI-sponsored 

research projects in each category can be found 

in Chapters 3 through 8 and Appendix B9.

Included in the graph are solicited and 

unsolicited projects and individual training and career development awards, both new and continuing, with breast 

cancer relevance values of 25% of more. (Solicited projects are those resulting from submissions in response to NCI 

initiatives in targeted topic areas; unsolicited projects are those resulting from the other submissions received by the 

NCI.)

Each project with 25% or greater relevance to breast cancer was counted once for each category to which it 

applied.10

0

100

200

300

400

500

600

1998 1999 2000 2001 2002 2003

Fiscal Year

Intramural Support and Contracts

Scientific Model Systems

Cancer Control, Survivorship, and Outcomes

Treatment

Early Detection, Diagnosis, and Prognosis

Prevention

Etiology

Biology

Figure 1-4. Dollar estimates for breast cancer-relevant research by type of research

Figure 1-5. Number of research projects 

relevant to breast cancer

0

500

1000

1500

2000

1998 1999 2000 2001 2002 2003

Fiscal Year

Number of Projects

8 Quantitative estimates of cancer-site relevance are made by NCI staff based on the proportion relevant to disease sites. The NCI uses relevance values for calculating 

prorated dollar allocations (as in Figure 1-3) and for project tracking.

9 Appendix B identifies the FY2003 research projects that were responsive to the PRG priorities.

10 Category assignment was based on the results of mapping projects to the 64 PRG recommendations and not on original CSO assignments. Projects that are assigned to 

more than one research category are included in the data for all appropriate categories.
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-5

Clinical Trials Supported

Between 1998 and 2003, the number 

of active NCI-sponsored clinical trials 

relevant to breast cancer increased. 

Figure 1-7 shows the increase in the 

overall number of NCI-sponsored11

clinical trials relevant to breast cancer 

that were active during the calendar 

years 1998 to 2003. These clinical 

trials represent research on treatment, 

prevention, genetics, diagnostics, and 

supportive care.

These data indicate overall numbers of 

breast cancer clinical trials. (Information 

in the figure is based on a search 

conducted by staff of the Office of 

Cancer Information Products and Systems, Office of Communications [in its PDQ Clinical Trials Database] for NCIsponsored breast cancer treatment trials active at some time during the timeframe 1998 to 2003.) More detailed information 

about specific trials is available on NCI’s Cancer.gov website at http://www.cancer.gov/clinical_trials.

Initiatives Undertaken

Between FY1998 and FY2003, numerous NCI initiatives supported work on the research priorities identified by the Breast 

Cancer PRG. The initiatives increased the depth and breadth of the NCI’s research on breast cancer by:

■ Encouraging submission of applications for research projects that are wholly or partially focused on breast cancer in targeted 

topic areas

■ Developing and maintaining resources for use by breast cancer researchers

■ Establishing and expanding programs in which research and resources are combined in collaborative pursuit of a common 

goal

Figure 1-6. Number of breast cancer-relevant projects addressing each research category

Figure 1-7. Number of NCI-sponsored breast cancer clinical trials active 

during calendar years 1998-2003

0

100

200

300

400

500

600

1998 1999 2000 2001 2002 2003

Fiscal Year

Number of Projects

Etiology

Prevention

Early Detection, Diagnosis, and Prognosis

Treatment

Cancer Control, Survivorship, and Outcomes

Biology

100

120

140

160

180

200

1998 1999 2000 2001 2002 2003

Calendar Year

11 An NCI-sponsored clinical trial in the Physician Data Query (PDQ): (1) has been reviewed and approved by NCI’s CTEP Protocol Review Committee or by an approved 

NCI-designated Cancer Center Protocol Review and Monitoring System, and/or (2) receives support through an NCI grant or cooperative agreement.
October 2004 NCI Breast Cancer Progress Report

1-6 Chapter 1: Breast Cancer Research, 1998-2003

Table 1-1 lists the NCI initiatives that resulted in breast cancer research in FY1998 through 200312 and identifies the chapter 

of this report in which more detail on the initiatives is provided.

Table 1-1. NCI Initiatives Relevant to Breast Cancer Research: 1998-2003

Initiatives Focused on Breast Cancer

Chapter 2: General Initiatives

■ Aging Women and Breast Cancer: PA-00-001 (continued in FY2000)

■ Breast and Ovarian Cancer Family Registries (CFRs): http://epi.grants.cancer.gov/BCFR/index.html (ongoing)

■ Breast Cancer Faculty: http://ccr.cancer.gov/faculties/faculty.asp?facid=129 (ongoing)

■ Breast Cancer Surveillance Consortium (BCSC): http://breastscreening.cancer.gov/ (ongoing)

■ Cooperative Breast Cancer Tissue Resource (CBCTR): http://www-cbctr.ims.nci.nih.gov/ (ongoing)

■ Insight Awards to Stamp Out Breast Cancer: PAR-99-128 (begun in 1999)

■ International Breast Cancer Screening Network (IBSN): http://appliedresearch.cancer.gov/ibsn/ (begun FY1998)

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer: http://spores.nci.nih.gov/breast/breast.html

(ongoing)

Chapter 3: Biology

■ Stages of Breast Development: Normal to Metastatic Disease: PA-99-162 (begun in 1999)

Chapter 4: Etiology

■ Breast Cancer and the Environment Research Centers: RFA-ES-03-001 (begun in 2003)

■ Long Island Breast Cancer Study Project: http://epi.grants.cancer.gov/LIBCSP/Overview.html (ongoing)

■ Regional Variation in Breast Cancer Rates in the U.S.: RFA-CA-98-017 (begun in 1998)

Chapter 5: Prevention

■ Chemoprevention of Estrogen Receptor-Negative Breast Cancer Preclinical Studies: RFA-CA-03-005

(begun in FY2002)

■ Study of Tamoxifen and Raloxifene (STAR) Trial: http://www.cancer.gov/star (begun in FY1999)

Chapter 6: Early Detection, Diagnosis, and Prognosis

■ Development of Digital Mammography Displays and Workstations: PA-99-082 and PA-99-083 (begun in 1999)

Initiatives With Breast Cancer-Relevant Components

Chapter 2: General Initiatives

■ Applications of Innovative Technologies for the Molecular Analysis of Cancer: PAR-01-106 and PAR-01-107

(begun in FY1999; continued in FY2001)

12 Initiatives selected for inclusion are those that were begun or continued during FY1998-2003 that resulted in programs, resources, or research projects relevant to breast 

cancer. Also selected for inclusion are ongoing NCI intramural initiatives that have a readily identifiable component that is specific to breast cancer.
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-7

■ Basic and Preclinical Research on Complementary and Alternative Medicine (CAM): PA-02-124 (begun FY2002)

■ Bioengineering Research Grants: PA-02-011 (begun FY1999)

■ Bioengineering Research Partnerships: PAR-03-032 (begun in FY1999)

■ Cancer Biomedical Informatics Grid (caBIG): http://cabig.nci.nih.gov/ (begun in FY2003)

■ Cancer Centers Program: www3.cancer.gov/cancercenters/ (ongoing)

■ Cancer Genetics Services Directory: http://www.cancer.gov/search/genetics_services/

■ Cancer Genome Anatomy Project (CGAP): http://cgap.nci.nih.gov/ (ongoing)

■ Cancer Imaging Program (CIP): http://www3.cancer.gov/dip (ongoing)

■ Cancer Molecular Analysis Project (CMAP): http://cmap.nci.nih.gov (ongoing)

■ Cancer Prognosis and Prediction: PAR-03-098 and PAR-03-099 (begun in FY2001; continued in FY2003)

■ Cancer Research Network (CRN): http://cancercontrol.cancer.gov/bb/can_research.html (begun in FY1998)

■ Cancer Research Small Grant Program: PAR-02-176 (ongoing; reissue of the Cancer Prevention Research 

Small Grant Program) 

■ Cancer Research Training, Career Development and Education Opportunities: http://cancertraining.nci.nih.gov/

(ongoing)

■ Clinical Trials Cooperative Group Program: http://ctep.cancer.gov/resources/coop2.html (ongoing) 

■ Community Clinical Oncology Program (CCOP): http://www3.cancer.gov/prevention/ccop (ongoing)

■ Competing Supplements for Organotypic Models of Cancer: PAR-02-052 (begun in FY2002)

■ Cooperative Human Tissue Network (CHTN): http://www-chtn.ims.nci.nih.gov/ (ongoing)

■ Correlative Studies Using Specimens from Multi-institutional Treatment Trials: PA-03-064

(begun in FY1998; continued in FY2001 and FY2003)

■ Developmental/Pilot Projects in Cancer Complementary and Alternative Medicine (CAM): PAR-02-040

(begun in FY2002)

■ Director’s Challenge: Toward a Molecular Classification of Tumors: http://dc.nci.nih.gov (begun in FY1999)

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials: PA-98-042 (ongoing)

■ Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses (FLAIR): 

http://dtp.nci.nih.gov/branches/gcob/gcob_web17.html (begun in FY1998; continued in FY2000 and FY2001)

■ Improving DNA, RNA and Protein Availability in Fixed Tissue: PAR-00-079 (begun FY2000)

■ In Vivo Cellular and Molecular Imaging Centers (ICMICs): http://www3.cancer.gov/bip/ICMICs.htm

(begun in FY1999)

■ Integrating Aging and Cancer Research: PA-02-169 (begun in FY2002)

■ Interdisciplinary Research Teams for Molecular Target Assessment: RFA-CA-00-001 (begun in FY2000)

■ Minority-Based Community Clinical Oncology Program (MBCCOP): 

http://www3.cancer.gov/prevention/ccop/mbccop.html (begun in FY2002)
October 2004 NCI Breast Cancer Progress Report

1-8 Chapter 1: Breast Cancer Research, 1998-2003

■ Minority Institution/Cancer Center Partnership (MI/CCP): http://minorityopportunities.nci.nih.gov/institutions/

(begun in FY2000) 

■ Molecular Target Drug Discovery for Cancer: PAR-01-045 and PAR-01-046 (begun in FY2000)

■ Mouse Models of Human Cancers Consortium: RFA-CA-98-013 (begun in FY1999)

■ NCI Center for Bioinformatics (NCICB): http://ncicb.nci.nih.gov

■ Non-Mammalian Organisms as Models for Anticancer Drug Discovery: PAR-99-019 and PAR-99-020

(begun in FY1999)

■ Program for the Assessment of Clinical Cancer Tests (PACCT): 

http://www.cancerdiagnosis.nci.nih.gov/assessment (begun in FY2000)

■ Shared Pathology Informatics Networks (SPIN): http://spin.nci.nih.gov/ (begun in FY2000)

■ Shared Resources for Scientists Outside NCI Cancer Centers: RFA-CA-01-020 (begun FY1999)

■ Small Animal Imaging Resource Program (SAIRP): http://www3.cancer.gov/dip/sairp.htm (begun FY1998)

■ Small Grants Program for Cancer Epidemiology: http://epi.grants.cancer.gov/ResPort/grants.html (ongoing)

■ Southern Community Cohort Study (SCCS): http://www.southerncommunitystudy.org (begun in FY2001)

■ Special Populations Networks (SPNs): http://crchd.nci.nih.gov/spn/index.html (begun FY1999)

■ Specimen Resource Locator: http://pluto3.nci.nih.gov/tissue/default.htm (ongoing) 

■ Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors: 

RFA-CA-01-011 (expanded in FY2001)

■ Therapeutic Modulation of Angiogenesis in Disease: PAR-98-096 (begun FY1998)

■ Unconventional Innovations Program (UIP): http://otir.cancer.gov/tech/uip.html (begun in FY1999)

Chapter 3: Biology

■ Bioengineering Nanotechnology Initiative: PA-02-125 (begun FY2000; continued in FY2002)

■ Complex Formation in Hormonal Regulation of Gene Expression: PA-02-100 (begun in FY2002)

■ Mammalian Gene Collection: http://mgc.nci.nih.gov/Info/Summary (begun in FY1999) 

■ Molecular and Cellular Biology of Metastatic Tumor Cells: PA-01-020 (begun in FY2001)

■ Molecular Interactions Between Tumor Cells and Bone: RFA-CA-03-013 (begun in FY2002)

■ Structural Biology of Membrane Proteins: PA-02-108 and PA-02-060 (ongoing)

Chapter 4: Etiology

■ Cancer Genetics Network (CGN): http://epi.grants.cancer.gov/CGN (ongoing)

■ Cohort Studies in Cancer Epidemiology: PAS-02-009 (begun in FY2002)

■ Diet, Lifestyle, and Cancer in U.S. Special Populations: PA-98-028 (begun in FY1998)

■ Geographic-Based Research in Cancer Control and Epidemiology: PAS-00-120 (begun in FY2000)

■ Interdisciplinary Studies in the Genetic Epidemiology of Cancer: RFA-CA-98-018 (begun in FY1998)

■ NCI Cohort Consortium: http://cancercontrol.cancer.gov/bb/cohort_conso.html (begun in FY2000)
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-9

Chapter 5: Prevention

■ Chemoprevention in Genetically-Identified High-Risk Groups: Interactive Research and Development Projects: 

RFA-CA-98-012 (begun in FY1998)

■ Phase I and II Cancer Prevention Clinical Trials Consortia: CN-25000-39 (begun in FY2002)

■ Rapid Access to Preventive Intervention Development (RAPID) Program: 

http://www3.cancer.gov/prevention/rapid/index.html (begun in FY2000)

Chapter 6: Early Detection, Diagnosis, and Prognosis

■ Cancer Diagnosis Program: http://www.cancerdiagnosis.nci.nih.gov (ongoing) 

■ Clinical Proteomics Program (CPP): http://ncifdaproteomics.com/index.php (begun in FY1999)

■ Development of Clinical Imaging Drug Enhancers (DCIDE): http://www3.cancer.gov/bip/DCID_des.htm

(begun in FY2000)

■ Development of Novel Technologies for InVivo Imaging: PAR-01-101 and PAR-01-102

(begun in FY2000 as the Development of Novel Imaging Technologies)

■ Diagnostic Imaging Network—American College of Radiology Imaging Network (ACRIN):

http://www.acrin.org/ (begun in FY1999)

■ Early Detection Research Network: http://www3.cancer.gov/prevention/cbrg/edrn (begun in FY1998)

■ Exploratory/Developmental Grants for Diagnostic Cancer Imaging: PA-01-030 (begun in FY1998)

■ Exploratory Studies in Cancer Detection, Prognosis and Prediction: PA-03-003 (begun in FY2001)

■ Exploratory Studies in Cancer Diagnostics: PA-98-022 (begun in FY1998)

■ Gene Expression Data Portal (GEDP): http://gedp.nci.nih.gov/dc/index.jsp (ongoing)

■ Innovative Technologies for the Molecular Analysis of Cancer: PAR-01-105 and PAR-01-104

(begun in FY1998; continued in FY1999 and FY2001)

■ Tissue Array Research Program (TARP): http://ccr.cancer.gov/tech_initiatives/tarp

Chapter 7: Treatment

■ Cancer Drug Discovery: Diversity Generation and Smart Assays: RFA-CA-98-009 (ongoing) 

■ Cancer Therapy-Related Use of Genetically Engineered Mice: PAR-02-051 (begun in FY2002)

■ Cancer Trials Support Unit: http://www.ctsu.org (ongoing)

■ Central Institutional Review Board: http://www.ncicirb.org/ (begun in FY2001)

■ Clinical Cancer Therapy Research: PA-02-002 (continued in FY1999)

■ Cooperative Planning Grant for Cancer Disparities Research Partnership: RFA-CA-03-018 (begun in FY2002)

■ Development and Application of Imaging in Therapeutic Studies: RFA-CA-98-024 (begun in FY1998)

■ Expanded Participation Project (EPP): http://spitfire.emmes.com/study/epp

■ National Cooperative Drug Discovery Groups (NCDDGs): http://dtp.nci.nih.gov/branches/gcob/gcob_web3.html

(continued in FY1999)

■ Quick Trials for Novel Cancer Therapies: PAR-03-005 (begun in FY2000)
October 2004 NCI Breast Cancer Progress Report

1-10 Chapter 1: Breast Cancer Research, 1998-2003

■ Rapid Access to Intervention Development (RAID) Program: http://dtp.nci.nih.gov/docs/raid/raid_index.html

(ongoing)

■ Rapid Access to NCI Discovery Resources (RAND): http://dtp.nci.nih.gov/docs/rand/rand_index.html (ongoing)

■ Translational Research Initiative (TRI): http://ctep.cancer.gov/resources/trf-overview.html (begun in FY2001)

Chapter 8: Cancer Control, Survivorship, and Outcomes

■ Basic Biobehavioral Research on Cancer-Related Behaviors: RFA-CA-99-014 (begun in FY2000)

■ Cancer Control PLANET: http://cancercontrolplanet.cancer.gov/ (begun FY2003)

■ Cancer Intervention and Surveillance Modeling Network (CISNET): http://cisnet.cancer.gov/about

(begun in FY1999; continued in FY2002)

■ Cancer Outcomes Measurement Working Group (COMWG): http://outcomes.cancer.gov/methods/measures/comwg

(begun in FY2001)

■ Cancer Surveillance Using Health Claims-Based Data System: http://dccps.nci.nih.gov/ARP/research/health.asp

(continued in FY1999)

■ Cancer Survivorship Studies in Established Epidemiologic Cohorts: PA-98-027 (begun in FY1998)

■ Centers for Complementary and Alternative Medicine Research: RFA-AT-00-001 (begun in FY1999)

■ Centers of Excellence in Cancer Communications Research: http://cancercontrol.cancer.gov/eocc/ (begun in FY2001)

■ Digital Divide Pilot Projects: http://cancercontrol.cancer.gov/eocc/ddpp_awards.html (begun in FY2000)

■ Economic Studies in Cancer Prevention, Screening, and Care: 

http://cancercontrol.cancer.gov/ARP/research/economic.asp (ongoing)

■ Exploratory Grants for Behavioral Research in Cancer Control: PA-99-163 (begun in FY1999)

■ Health Communications in Cancer Control: RFA-CA-98-014 (begun in FY1998)

■ Long-Term Cancer Survivors: Research Initiatives: RFA-CA-04-003 (begun in FY1998)

■ Minority and Underserved Cancer Survivors: http://cancercontrol.cancer.gov/ocs/underserved

■ Research on the Impact of Cancer on the Family: http://dccps.nci.nih.gov/bb/research_family.html

■ Research Supplements for Underrepresented Minorities: http://cancercontrol.cancer.gov/ocs/underrepresented/

■ SEER-Medicare Linked Database: http://healthservices.cancer.gov/seermedicare (ongoing)

■ SEER Patterns of Care/Quality of Care (POC/QOC) Initiative: http://cancercontrol.cancer.gov/bb/seer_pattern.html

(begun FY2001)

■ Small Grants Program for Behavioral Research in Cancer Control: http://dccps.nci.nih.gov/smallgrants/index.html

(ongoing)

■ Social and Cultural Dimensions of Health: PA-02-043 (begun in FY2002)

■ Surveillance, Epidemiology, and End Results (SEER): http://seer.cancer.gov (expanded in FY2001)

■ Translating Research into Improved Outcomes (TRIO): http://cancercontrol.cancer.gov/bb/trio.html
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-11

Resources for Breast Cancer Research That Were Developed, Maintained, or Expanded

NCI-funded resources that support breast cancer research include the following:

■ Repositories for accessing biological specimens and associated clinical data from patients with breast cancer and women at 

risk of developing the disease

■ Databases for accessing information from multiple sources

■ Animal models that mimic the development and/or progression of breast cancer

■ Forums for communicating research results and stimulating discussion and collaboration among investigators

■ Training programs for improving the skills and advancing the careers of young, mid-career, and minority investigators

■ Tools for assisting investigators in locating research resources

■ Rapid development of new technologies

■ Conduct of large, multi-institutional clinical trials

■ Access to specialized patient populations

■ Access to specialized equipment and expertise

Examples of NCI-supported resources include the following:

■ Cancer Research Training, Career Development, and Education Opportunities

■ Cooperative Breast Cancer Tissue Resource

■ Mouse Models of Human Cancers Consortium (MMHCC)

■ Mammary Gland Cancer Committee

■ Mouse Models Repository

■ Clinical Trials Cooperative Group Program

■ American College of Radiology Imaging Network (ACRIN)

■ Early Detection Research Network (EDRN) (which includes a Breast and Gynecologic Cancers Collaborative Group)

■ Minority Institution/Cancer Center Partnership (MI/CCP)

■ Rapid Access to Intervention Development (RAID) Program

In addition, Specialized Programs of Research Excellence (SPOREs) in Breast Cancer provide a comprehensive mix of 

translational research projects,13 core resources, and training opportunities. Details about these SPOREs can be found in 

Chapter 2.

13 Translational research aims to move findings from the basic laboratory into the clinical setting.
October 2004 NCI Breast Cancer Progress Report

1-12 Chapter 1: Breast Cancer Research, 1998-2003

Research Progress

One indicator of research progress is growth in the number of peer-reviewed publications on a specific topic. Figure 1-8 (page 

12) shows the estimated number of peer-reviewed publications indicating NCI support and relevance to breast cancer during 

calendar years 1998 through 2003. The values in Figure 1-8 should be considered conservative estimates.14

Table 1-2 lists areas of ongoing NCI-sponsored research that are represented in recent publications. The table also includes the 

report chapter in which progress in these areas is highlighted.

Table 1-2. Recent Progress in Breast Cancer Research

Initiatives (Chapter 2)

■ Specialized Programs of Research Excellence 

(SPOREs)

◆ Krüppel-Like Transcription Factor (KLF4) Protein 

as a Biomarker

◆ Novel Liposome Constructs for Drug Delivery

◆ Collaborative Study of Magnetic Resonance 

Imaging to Measure Response to Chemotherapy

◆ AVON Foundation-NCI Progress for Patients 

Awards Program

Biology (Chapter 3)

■ Mammary Gland Development and Breast Cancer 

Susceptibility

◆ Breast Cancer Stem Cells

◆ Mouse and Multicell Model Systems

■ Genetic and Epigenetic Changes in Breast Cancer 

Development

◆ BRCA1 Tumor-Suppressor Gene

◆ Her2/neu-Receptor Tyrosine Kinase

Figure 1-8. Estimated number of peer-reviewed publications on breast cancer acknowledging NCI support

Values are the total unique publications identified from a MEDLINE search and an ISI/Web of Science search. (Both databases 

were queried using the following criteria: (1) using terms related to “breast”; (2) including an NCI grant number or author 

address; and (3) limiting to publications in an English-language, peer-reviewed journal. An additional search in MEDLINE for 

all grant numbers representing 100% breast cancer-relevant projects was performed in the grant number field using the same 

limitations. Both intramural and extramural NCI projects are represented.)

0

400

800

1200

1600

2000

1998 1999 2000 2001 2002 2003

Year

Number of Publications

14 Given such factors as less-than-complete support acknowledgments by authors, inclusion of only the corresponding author’s affiliation in MEDLINE, possible typographic 

errors in reporting grant numbers, possible data entry errors, and journal policies on support acknowledgments, the publication counts reported in Figure 1-8 are no doubt 

underestimates.
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-13

■ Metastasis and Progression

◆ Factors Responsible for Osteolysis

◆ Models of Metastasis

Etiology (Chapter 4)

■ BRCA1 and BRCA2

◆ Risk of Breast Cancer in Mutation Carriers

◆ Modifiers of Breast Cancer Risk Among Carriers

■ Other Breast Cancer Susceptibility Genes

◆ CHEK2

◆ ATM Gene

■ Environmental Influences

■ Behavioral Factors

◆ Hormone Replacement Therapy

◆ Obesity

■ Endogenous Factors

Prevention (Chapter 5)

■ Models of Precancerous Biology

◆ Neu Transgenic Mouse

◆ Conditional Knockout of the BRCA1 Gene in the 

Mammary Epithelium of Mice

■ Dietary Factors

◆ Low-Fat Diet

◆ Natural Products (e.g., Green Tea Polyphenol 

Epigallocatechin-3 Gallate)

■ Prevention Trials

◆ Selective Estrogen-Receptor Modulators

◆ Retinoids

Detection, Diagnosis, and Prognosis (Chapter 6)

■ Imaging Technologies

◆ Positron Emission Tomography

◆ Magnetic Resonance Imaging

◆ Convolution Neural Networks

◆ Automated Estimation Analysis Tool to Estimate 

Mammographic Breast Density

■ Novel Biologic Markers

◆ Mammaglobin Gene

◆ Epidermal Growth Factor Receptor

◆ 2,6-Cyclolycopene-1,5-Diol

◆ Combinations of Markers Identified by Microarray

◆ Estrogen Receptor and A1B1 (SRC-3) Protein 

Expression to Predict Response to Tamoxifen 

Treatment

Treatment (Chapter 7)

■ Progress in Preclinical Models

◆ C3(1)/SV40 Tag Mice

■ In Situ Disease

◆ Postsurgical Tamoxifen

◆ Postoperative Anastrazole

■ Operable Disease

◆ Adjuvant Treatment for Node-Negative Patients

◆ Oncotype Dxtm Breast Cancer Assay

◆ Preoperative Chemotherapy

◆ Breast-Conserving Surgery and Quality of Life

◆ Chemotherapy Intervals

◆ Aromatase Inhibitors

■ Nonoperable Disease

◆ Ongoing Clinical Trials With Chemo- and Biologic 

Therapies

Cancer Control, Survivorship, and Outcomes 

Research (Chapter 8)

■ The Importance of Mammography

◆ Tailored Communications

◆ The Use of Screening Mammography

■ Factors Affecting the Accuracy of Mammography

◆ Breast Density

◆ Breast Positioning During the Mammogram
October 2004 NCI Breast Cancer Progress Report

1-14 Chapter 1: Breast Cancer Research, 1998-2003

■ Quality of Care

◆ Barriers to Appropriate Follow-Up

◆ Disparities in the Care of Women With Breast 

Cancer

■ Survivors’ Issues

◆ Physical Symptoms After Completing Treatment

◆ Social Support and Well-Being

◆ Health Behaviors

◆ Indirect Morbidity and Disability Costs of Breast 

Cancer

Applied Research

NCI-sponsored research has led to new and innovative prevention and treatment interventions. In 1998, for example, 

tamoxifen became the first drug to receive U.S. Food and Drug Administration15 (FDA) approval for the prevention of breast 

cancer in high-risk women. Two other drugs, anastrozole (Arimidex®) and letrozole (Femara®), received approval as firstline treatments for postmenopausal women with locally advanced or metastatic breast cancer. Anastrozole was also approved 

for the adjuvant treatment of postmenopausal women with early breast cancer. The FDA also approved taxanes (paclitaxel 

[Taxol®] and docetaxel [Taxotere®]) and epirubicin (EllenceTM) for women with axillary node involvement. Other drugs have 

been approved for the treatment of metastases associated with breast cancer. In particular, zoledronic acid (Zometa®) and 

pamidronate (Aredia®) are now used to treat bone metastases and trastuzumab (Herceptin®) is used for patients whose tumors 

overexpress the Her2/neu gene.

Patients with advanced breast cancer now have more treatment options than ever before. For hormone-sensitive tumors, 

fulvestrant (Faslodex®) and exemestane (Aromasin®) are second-line choice, while a series of new agents—capecitabine 

(Xeloda®), gemcitabine (Gemzar®), and vinorelbine (Navelbine®)—are new chemotherapeutics able to offer palliation once 

hormonal therapies become ineffective.

Newer practices related to surgical management of breast cancer have become more accepted.16 While axillary lymph node 

dissection remains the standard practice for staging lymph nodes, sentinel lymph node biopsy is receiving greater recognition as 

an alternative that has the potential to reduce the side effects associated with axillary lymph node dissection. A definitive trial 

(NSABP B-32) supported by NCI comparing the two approaches has completed accrual of more than 5,000 patients. When 

available, results from this comparison will prove whether or not the sentinel node technique produces comparable survival 

results with fewer side effects.

Preoperative (neoadjuvant) therapy can reduce the size of a large tumor, thereby allowing more women to undergo breastconserving therapy. This approach also holds the appealing possibility of providing for more tailored therapy according to the 

biologic characteristics and responsiveness of individual tumors. NCI-supported studies are currently enrolling patients on 

trials testing this novel approach, and these studies are collecting valuable tissue specimens that will be key to an understanding 

of tumor responsiveness and resistance to specific therapies. More details about preoperative therapy are presented in the 

Ongoing NCI Research: Operable Disease section of Chapter 7.

U.S. patents issued each year with relevance to breast cancer show promise for future product development. Investigators 

supported by the NCI have translated their basic discoveries into advances in technology. Between 1998 and 2003, 96 patents 

15 Information on breast cancer-related drugs approved by the FDA between 1998 and 2003 was obtained from the FDA’s Oncology Tools Web site at http://www.fda.gov/

search/databases.html. 

16 The American College of Radiologists (ACR) published guidelines on sentinel lymph node biopsy and preoperative therapy in the “Standards for breast conservation 

therapy in the management of invasive breast carcinoma.” This document and other guidelines can be found on the National Guideline Clearinghouse Web site 

(www.guideline.gov).
NCI Breast Cancer Progress Report October 2004

Chapter 1: Breast Cancer Research, 1998-2003 1-15

relevant to breast cancer were awarded or were pending decisions by the U.S. Patent Trademark Office (USPTO).17 A listing of 

these patents can be found in Appendix C, including patents for:

■ Advances in breast imaging devices

■ Biomarker-based diagnostic and prognostic indicators

■ Methods of inhibiting cancer growth

■ Assays for tumor proliferative status

■ Genetic markers for cancer

■ Novel delivery systems for anticancer agents

This Progress Report

This report, which documents the NCI’s responsiveness to the recommendations of the Breast Cancer PRG report over 

the years 1998 through 2003, will be used by the NCI to help the Institute make course corrections and develop new 

recommendations regarding breast cancer research. The report is organized according to the CSO18 categories used by the NCI:

■ Initiatives

■ Biology

■ Etiology

■ Prevention

■ Early Detection, Diagnosis, and Prognosis

■ Treatment

■ Cancer Control, Survivorship, and Outcomes

Chapter 2 provides details on NCI initiatives that address multiple categories of breast cancer research, along with the specific 

programs, resources, and/or research projects that derive from those initiatives. In Chapters 3 through 8, progress is reported 

for both a specific research category as a whole and for the underlying individual PRG investigative priorities. Quantitative 

measures are included throughout to demonstrate the extent of the NCI’s responsiveness to the PRG research priorities.

This report addresses only part of the progress made since 1998, with the content limited to NCI-sponsored research that is 

most relevant to breast cancer. In addition to the NCI, other federal and nonfederal agencies fund research on breast cancer. 

Furthermore, human cancers are complex diseases; each cancer site has features that are unique and features that are shared 

with other cancer sites. It is possible that the solution for preventing breast cancer or the suffering and death resulting from this 

disease will ultimately derive from research directed at another cancer site, or even from research directed at a noncancerous 

disease. To increase the likelihood that significant breakthroughs will be made in prevention, diagnosis, and treatment, the NCI 

remains committed to planning, conducting, and assessing research that is directed specifically at breast cancer while remaining 

ever vigilant for cross-cutting advances from other tumors or disciplines.

17 Patents and patent applications were identified by searching the USPTO databases (http://www.uspto.gov/patft/index.html) for breast-relevant terms and then selecting for 

projects in which the government interests/rights were attributed to grants that included the NCI’s Administering Organization Code.

18 Scientific model systems was not included as a unique chapter in this report due to the small number of priorities addressing this topic in the PRG’s original report and 

the overlapping relevance of this category to other research categories. Significant advances in models research are presented in the chapters on biology, prevention, and 

treatment.

NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-1

Chapter 2:

Initiatives

The current mechanism of peer-reviewed, investigator-initiated research project grants has served us 

very well over the years. This approach should be continued and enhanced.... Additional pathways are 

needed, however, to support important research not currently well served by existing mechanisms. 

Charting the Course: Priorities for Breast Cancer Research

As the leader of the National Cancer Program, the NCI provides vision and direction to the nationwide community of 

researchers, public health workers, health care providers, patients, advocates, and policy makers working to defeat cancer. In 

this capacity, the NCI is responsible for coordinating, conducting, and funding programs in basic research, training, and public 

health that pertain to the diagnosis, prevention, and treatment of cancer.

The largest share of NCI funding for biomedical research supports investigator-initiated applications. This approach enables 

individual scientists to design and focus on research projects that they believe have the greatest significance and offer the best 

chance of producing important knowledge. The investigator-initiated cancer research portfolio extends broadly across research 

fields and disciplines.

Research is also solicited and resources are developed through the use of initiatives, which encourage work in priority areas, 

support multidisciplinary research collaborations, and generate research applications in areas that are not addressed adequately. 

Initiatives permit the NCI to take advantage of scientific opportunities in a timely way. They also provide funding to overcome 

barriers to progress and allow investigators to pursue new research that is outside their area of expertise. Initiatives soliciting 

breast cancer research are used by the NCI to address priorities that might not otherwise be addressed through investigatorinitiated research proposals. In the broadest sense, initiatives include the following:

■ The extramural funding opportunities used for establishing new projects, resources, and programs

■ The resources and programs that result from these funding opportunities

■ The resources and programs that the NCI establishes within its intramural programs

A recurring theme throughout the 1998 Breast Cancer PRG report was that progress in highly promising avenues of breast 

cancer research is being delayed because of limitations in knowledge, resources, infrastructure, or capacity needed for 

conducting this work. To address these limitations, PRG members generated a list of the most important scientific priorities 

and recommended actions in breast cancer biology, etiology, genetics, prevention, detection, treatment, cancer control, and 

outcomes. These topics are addressed in Chapters 3-8 of this report. In addition to these recommendations, the 1998 Breast 

Cancer PRG identified 13 critical areas of equal priority spanning the continuum of breast cancer research and care:

■ Increase basic research on the biology and developmental genetics of the normal mammary gland.

■ Develop better model systems for breast cancer.

■ Increase research on the genetics and biology of precancerous lesions and their progression to invasive, metastatic cancers.

■ Identify key biomarkers and surrogate endpoints for epidemiologic studies and prevention and therapy trials.

■ Enhance availability of new technologies and funding for equipment.

■ Facilitate novel therapeutic approaches in academic health centers and via public/private partnerships.

■ Modify and enhance support for prevention and therapy clinical trials.

■ Ensure that all breast cancer basic and clinical research and communications efforts reflect and address patient and survivor 

needs and concerns.
October 2004 NCI Breast Cancer Progress Report

2-2 Chapter 2: Initiatives

■ Increase focus on and support for basic and applied research into biobehavioral mechanisms and decision making relevant to 

cancer prevention, detection, and treatment.

■ Expand training opportunities and support, especially for multidisciplinary training of translational investigators and to 

attract new talent to breast cancer research.

■ Promote multidisciplinary research focus and communication.

■ Develop mechanisms to support innovation and enhance support for specific areas of research.

■ Address informed consent and confidentiality issues.

The NCI has responded to the 1998 PRG priorities and recommendations by expanding its investment in solicited breast 

cancer research. By expanding ongoing initiatives and introducing new initiatives targeting priority research topics, the NCI 

provides focused support and guidance for researchers pursuing breast cancer studies. By supporting initiatives that provide 

infrastructure and resources, the NCI facilitates research projects that rely on centralized, shared resources and collaborations. 

Many of these initiatives and resources are, appropriately, not limited to or specific for breast cancer, but their availability 

facilitates the efforts of those focusing on breast cancer research.

NCI’s Investment and Response

Chapter 1 shows the growth in NCI spending on breast cancer research (Figure 1-3) and lists the specific initiatives that 

addressed breast cancer (Table 1-1) during the period 1998-2003. In this chapter, detailed information is provided for 

initiatives that are relevant to more than one research category. This information includes a description of the initiative, 

relevant research categories, and the program, resource, research projects, and/or products that resulted from the initiative 

(Table 2-1). For each initiative in Table 1-1 that applies to a single research category, more detail is provided in the report 

chapter that corresponds to the category.

Table 2-1. NCI Initiatives Relevant to Breast Cancer Research: Initiatives Affecting Multiple Research Categoriesa

Initiatives Focused on Breast Cancer

■ Aging Women and Breast Cancer (PA-00-001)

◆ Overview: Supports research that focuses on the unique problems of older women with breast cancer.

◆ Research Categories: All.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, 11 projects relevant to breast cancer research 

were supported. Specific projects can be found in Appendix B, Tables B2, B9, B16, B23, B33, B40, B41, B43, B46, 

B51, B54, and B55, by searching for the current PA number and the previously issued PA number (PA-96-034).

■ Breast and Ovarian Cancer Family Registries (CFRs) (http://epi.grants.cancer.gov/BCFR/index.html)

◆ Overview: Maintains tissue specimens and treatment information provided by over 9,000 families with a history of 

breast or ovarian cancer.

◆ Research Categories: Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment; Cancer Control, 

Survivorship, and Outcomes.

◆ Relevant Resource Related to This Initiative: The CFR resources are available to researchers to support studies in 

genetic epidemiology, clinical investigations, social and behavioral epidemiology, and health policy research. CFR 

data were used in more than 100 published reports between 1998 and 2003.

a. Lists of projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiatives Database.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-3

■ Breast Cancer Faculty (http://ccr.cancer.gov/faculties/faculty.asp?facid=129)

◆ Overview: Facilitates interactions among basic, epidemiological, translational, and clinical researchers in the 

NCI intramural research program in an effort to promote a community of investigators working together for the 

prevention, diagnosis, and cure of breast cancer. More than 200 NCI and NIH faculty members participate in a 

monthly seminar series and annual retreat to facilitate communication and collaborations among laboratories.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Program Resulting From This Initiative: Recent accomplishments include the establishment of consensus 

nomenclature for the comparative pathology of genetically engineered mouse and human breast lesions and the 

development of the NCI Mouse Model for Mammary Cancer Collective, which is a component of the Mouse 

Models of Human Cancers Consortium.

■ Breast Cancer Surveillance Consortium (BCSC) (http://breastscreening.cancer.gov/)

◆ Overview: Supports studies that investigate the factors influencing screening mammography performance in 

community practice. In addition to conducting research that evaluates screening mammography and its effect in 

populations, BCSC is actively collaborating with federal regulatory agencies, radiological professional societies, and 

private-sector vendors to reduce the cost and improve the quality of screening mammography performance. BCSC 

reviews and comments on reports and initiatives by these agencies, as well as collaborates in standardizing data 

collection for mammography quality control. BCSC relies on a Statistical Coordinating Center (RFA-CA-98-025) 

to serve as the central repository for pooled data and to provide the research expertise on complex statistical issues 

for analysis of these pooled data.

◆ Research Categories: Prevention; Early Detection, Diagnosis, and Prognosis; Cancer Control, Survivorship, and 

Outcomes.

◆ Relevant Projects Resulting From This Initiative:

Breast Cancer Surveillance in a Defined Population

Carolina Mammography Registry

Colorado Mammography Project

New Hampshire Mammography Network

New Mexico Mammography Project

San Francisco Mammography Registry

Statistical Coordinating Center

Vermont Breast Cancer Surveillance System

■ Cooperative Breast Cancer Tissue Resource (CBCTR) (http://www-cbctr.ims.nci.nih.gov/)

◆ Overview: Facilitates large research studies requiring archival tissue by supplying investigators with primary breast 

cancer tissues and associated clinical data.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Resources Resulting From This Initiative: Investigators can search an online database to identify breast 

cancer specimens that meet their specific research needs. Searches can be made based on annotated clinical 

characteristics, which include but are not limited to stage of disease, recurrence information, and treatment received, 

as well as resource characteristics, including the availability of normal (control) tissue.
October 2004 NCI Breast Cancer Progress Report

2-4 Chapter 2: Initiatives

■ Insight Awards to Stamp Out Breast Cancer (PAR-99-128)

◆ Overview: Supports innovative pilot studies to generate a new understanding of breast cancer. The focus of the 

program is to advance underdeveloped areas of research that were identified by the NCI Breast Cancer Progress 

Review Group.

◆ Research Categories: All.

◆ Relevant Products Resulting From This PA: Between 1998 and 2003, 47 projects relevant to breast cancer research 

were supported through this PA.b

■ International Breast Cancer Screening Network (IBSN) (http://appliedresearch.cancer.gov/ibsn/)

◆ Overview: Supports collaborative research aimed at identifying and fostering effective approaches to worldwide 

breast cancer control through population-based screening mammography.

◆ Research Categories: Early Detection, Diagnosis, and Prognosis; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Program Resulting From This Initiative: Representatives from 25 countries work together to compare 

data from international breast cancer screening programs and to develop methods for evaluating the impact of 

population-based breast cancer screening programs. Working groups within this consortium include the following:

Case Control Evaluation Group

Communications Working Group

Group on Assessment of Organized Screening Programs

Mortality Evaluation Group

Performance Parameters Evaluation Group

Quality Assurance Group

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer (http://spores.nci.nih.gov/breast/breast.html)

◆ Overview: Supports translational research centers that focus on the prevention, etiology, screening, diagnosis, and 

treatment of a specific organ-site cancer.

◆ Research Categories: All.

◆ Relevant Program Resulting From This Initiative: There are currently ten breast cancer SPORE sites, which are listed 

in Table 2-2. Yearly meetings are held to facilitate communication among the researchers participating in the breast 

cancer SPOREs and among the researchers participating in SPOREs for all cancer types.

Initiatives With Breast Cancer-Relevant Components

■ Applications of Innovative Technologies for the Molecular Analysis of Cancer (PAR-01-106; PAR-01-107)

◆ Overview: Supports research projects that evaluate and implement molecular analysis technologies in studies relevant 

to cancer research.

◆ Research Categories: Biology; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Research Projects Resulting From These PAs: Between 1998 and 2003, 16 projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Tables B1, B2, B5, B10, B14, B19, B26, and 

B29-33, by searching for these current PA numbers and the previously issued PA numbers (PAR-99-102 and PAR99-103).

b. Lists of projects derived from initiatives can be found in the online Supplement to the Breast Cancer Progress Report: Initiatives Database.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-5

■ Basic and Preclinical Research on Complementary and Alternative Medicine (CAM) (PA-02-124)

◆ Overview: Provides support for CAM and conventional researchers to focus on basic, mechanistic, and preclinical 

research on Complementary and Alternative Medicine-based treatments for diseases such as breast cancer.

◆ Research Categories: Prevention; Treatment; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Projects Resulting From This PA: Pending–this PA will remain open until July 15, 2005.

■ Bioengineering Research Grants (PA-02-011)

◆ Overview: Supports multidisciplinary research performed in a single laboratory or by a small number of investigators 

that applies an integrative systems approach to develop knowledge and/or methods to prevent, detect, diagnose, or 

treat disease or to understand health and behavior.

◆ Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, six projects relevant to breast cancer research 

were supported. Specific projects can be found in Appendix B, Tables B17, B18, B34, B51, B53, B54, and B56, by 

searching for the current PA number and the previously issued PA number (PAR-99-009).

■ Bioengineering Research Partnerships (PAR-02-010)

◆ Overview: Supports the formation of multidisciplinary research partnerships among multiple institutions that apply 

an integrative systems approach to develop knowledge and/or methods to prevent, detect, diagnose, or treat disease 

or to understand health and behavior.

◆ Research Categories: Biology; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, eight projects relevant to breast cancer research 

were supported. Specific projects can be found in Appendix B, Tables B2, B26, B29, B30, and B39, by searching for 

the current PA number and the previously issued PA numbers (PA-01-024, PAS-00-006, and PAS-99-010).

■ Cancer Biomedical Informatics Grid (caBIG) (http://cabig.nci.nih.gov/)

◆ Overview: Provides greater access to data, sharing of informatics tools and resources, and enables collaborations 

that span across laboratories and institutions. This grid is planned to be capable of expanding beyond the current 

proposed uses of clinical trials management, basic and clinical research support and data sharing, and tissue bank 

and pathology support.

◆ Research Categories: All.

◆ Relevant Resources Resulting From This Initiative: caBIG supports a variety of research applications, including 

the cancer Image Database (caIMAGE), cancer Model Organisms Database (caMOD), Cancer Central Clinical 

Database (C3D), and cancer Laboratory Information Management System (caLIMS). Original NCI databases 

such as the cancer Data Standards Repository (caDSR), Common Data Elements (CDE), CGAP, and CMAP are 

available to researchers through caBIG, as are tools and applications developed by partner institutions.

■ Cancer Centers Program (www3.cancer.gov/cancercenters/)

◆ Overview: Supports major academic and research institutions throughout the United States to sustain broad-based, 

coordinated, interdisciplinary programs in cancer research.

◆ Research Categories: All.

◆ Relevant Programs Resulting From This Initiative: More than 60 institutions have been awarded P30 Cancer 

Center Support Grants (CCSG) to fund the scientific infrastructure of their cancer centers. Support is provided for 
October 2004 NCI Breast Cancer Progress Report

2-6 Chapter 2: Initiatives

elements such as scientific leadership and administration, research resources that give ready access to state-of-the art 

technologies, and flexible funds that help the center pursue its planned objectives and take immediate advantage of 

new research opportunities.

■ Cancer Genetics Services Directory (http://www.cancer.gov/search/genetics_services/)

◆ Overview: Supports a directory of individuals who provide services related to cancer genetics, including cancer risk 

assessment, genetic counseling, and genetic susceptibility testing.

◆ Research Categories: Etiology; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Resource Resulting From This Initiative: Individuals contemplating genetic testing can locate a genetics 

counselor by searching an online directory. More than 370 genetics professionals specializing in breast cancer are 

listed in the United States and Canada.

■ Cancer Genome Anatomy Project (CGAP) (http://cgap.nci.nih.gov/)

◆ Overview: Supports a collaborative program for determining the gene expression profiles of normal, precancerous, 

and cancerous cells.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis.

◆ Relevant Resource Resulting From This Initiative: Through the CGAP Web site, researchers can access human and 

mouse genomic data, informatics tools, and information on methods and resources. The database has more than 

20,000 expressed genes from normal or cancerous human mammary tissue. The SAGE Genie Anatomic Viewer tool 

allows scientists to identify genes uniquely expressed in specific cancers, including breast cancer.

■ Cancer Imaging Program (CIP) (http://www3.cancer.gov/dip)

◆ Overview: Encompasses multiple initiatives that support cancer-related basic, translational, and clinical research in 

imaging sciences and technology.

◆ Research Categories: Biology; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Programs Resulting From This Initiative: Breast cancer research has been supported through Requests for 

Applications (RFAs) for the following programs:

Development and Application of Imaging in Therapeutic Studies

Development and Testing of Digital Mammography Displays and Workstations

Exploratory/Developmental Grants for Diagnostic Cancer Imaging

In Vivo Cellular and Molecular Imaging Centers (ICMICs)

Planning Grants for In Vivo Cellular and Molecular Imaging Centers (Pre-ICMICs)

Small Animal Imaging Resource Programs (SAIRPs)

■ Cancer Molecular Analysis Project (CMAP) (http://cmap.nci.nih.gov)

◆ Overview: Provides access to information regarding various aspects of cancer molecular biology, including molecular 

signatures for specific cancer types, molecular targeted agents, and clinical trials evaluating these agents.

◆ Research Categories: Biology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Resource Resulting From This Initiative: Data can be retrieved from the CMAP Web site for many types of 

cancer, including breast cancer.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-7

■ Cancer Prognosis and Prediction (PAR-01-061; PAR-01-062)

◆ Overview: Supports the development of new strategies for determining prognosis or predicting response to cancer 

therapy.

◆ Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Research Projects Resulting From These PAs: Between 1998 and 2003, five projects relevant to breast 

cancer research were supported. Specific projects can be found in Appendix B, Tables B29 and B33, by searching for 

these PA numbers.

■ Cancer Research Network (CRN) (http://cancercontrol.cancer.gov/bb/can_research.html)

◆ Overview: Supports research on cancer prevention, early detection, long-term care, and postdiagnosis monitoring.

◆ Research Categories: Early Detection, Diagnosis, and Prognosis; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Resource Resulting From This Initiative: Comprising 11 managed care research organizations, the CRN is 

developing integrated data systems to support studies that include evaluation of breast and cervical cancer screening 

and prophylactic mastectomy for women at high risk for breast cancer.

■ Cancer Research Small Grant Program (PAR-02-176) and Cancer Prevention Research Small Grant Program 

(PAR-00-025)

◆ Overview: Supports research in the fields of early detection, chemoprevention, biomarker development, and 

nutrition science. Short-term awards provide support for pilot projects, development and testing of new 

methodologies, or innovative projects that provide a basis for more extended research.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis.

◆ Relevant Research Projects Resulting From These PAs: Between 1998 and 2003, 30 projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Tables B1-3, B6-17, B19, B21, B23, B30, 

B31, and B36, by searching for these PA numbers.

■ Cancer Research Training, Career Development, and Education Opportunities (http://cancertraining.nci.nih.gov/)

◆ Overview: Supports predoctoral and postdoctoral training and faculty career development in the field of cancer 

research.

◆ Research Categories: All

◆ Relevant Resource Resulting From This Initiative: More than ten types of awards exist to support training and 

career development in cancer biology, causation, prevention and control, detection and diagnosis, treatment, and 

rehabilitation research. The number of breast cancer-relevant individual training and career development awards 

nearly doubled between the years FY1998 and FY2003.

■ Clinical Trials Cooperative Group Program (http://ctep.cancer.gov/resources/coop2.html)

◆ Overview: Supports organizations that generate and conduct clinical trials consistent with national priorities for 

cancer research.

◆ Research Categories: Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment; Cancer Control, 

Survivorship, and Outcomes.

◆ Relevant Resource Resulting From This Initiative: The cooperative groups include 14 member organizations, with 

11 currently conducting trials on breast cancer. Banked tissue resources are available to investigators through each 

cooperative group.
October 2004 NCI Breast Cancer Progress Report

2-8 Chapter 2: Initiatives

■ Community Clinical Oncology Program (CCOP) (http://www3.cancer.gov/prevention/ccop)

◆ Overview: Supports a comprehensive clinical trials mechanism for disseminating the latest cancer prevention and 

treatment research findings at the community level.

◆ Research Categories: Prevention; Treatment; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Program Resulting From This Initiative: The CCOP includes 17 funded groups of hospitals or private 

practices that participate in NCI-funded clinical trials. Ten of these groups are currently participating in trials on 

breast cancer.

■ Competing Supplements for Organotypic Models of Cancer (PAR-02-052)

◆ Overview: Supports the development and use of novel organ-like model systems that more closely resemble normal 

tissue or emerging tumors than do simple tissue culture systems.

◆ Research Categories: Biology; Etiology; Prevention.

◆ Relevant Projects Resulting From This PA: Pending.

■ Cooperative Human Tissue Network (CHTN) (http://www-chtn.ims.nci.nih.gov/)

◆ Overview: Supports the collection and distribution of benign, precancerous, and cancerous human tissue specimens 

for basic and developmental studies in cancer research.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Resource Resulting From This Initiative: Six member institutions currently coordinate the collection and 

distribution of specimens that include tissues obtained at surgery and autopsy, serum, and DNA/RNA. A Breast 

Tissue Progression Microarray is available in collaboration with CBCTR.

■ Correlative Studies Using Specimens from Multi-Institutional Treatment Trials (PA-03-064)

◆ Overview: Supports correlative studies using tumor specimens collected during multi-institutional trials. 

Potential studies may address the genetic variations and molecular changes within a cell, discovery of new cancer 

interventions, and promotion of translational research.

◆ Research Categories: Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, seven projects relevant to breast cancer research 

were supported. Specific projects can be found in Appendix B, Tables B2, B29, B30, B34, and B36, by searching for 

the current PA number and the previously issued PA numbers (PA-98-099 and PA-01-015).

■ Developmental/Pilot Projects in Cancer Complementary and Alternative Medicine (CAM) (PAR-02-040)

◆ Overview: Encourages and supports the development of basic and clinical (prevention, therapeutic, and palliative) 

CAM cancer research. Another goal of this initiative is to facilitate communication and collaboration between the 

CAM practitioner and the conventional cancer research communities.

◆ Research Categories: Treatment; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, six projects relevant to breast cancer research 

were supported. Specific projects can be found in Appendix B, Tables B33, B39, B41, B51, and B53, by searching 

for the PA number.

■ Director’s Challenge: Toward a Molecular Classification of Tumors (http://dc.nci.nih.gov)

◆ Overview: Supports the scientific community in an effort to redefine tumor classifications using molecular rather 

than morphological criteria.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-9

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis.

◆ Relevant Resource Resulting From This Initiative: The Director’s Challenge program Web site provides researchers 

with information, analytical tools, and microarray data sets. The Molecular Portraits of Human Breast Tumors

microarray data set is available. Between 1998 and 2003, two projects relevant to breast cancer research were 

supported through RFA-CA-98-027. Specific projects can be found in Appendix B, Tables B2, B29, and B30, by 

searching for the RFA number.

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials (PA-98-042)

◆ Overview: Supports the development of innovative therapeutic clinical trials or new correlative laboratory studies 

using patient specimens from therapeutic clinical studies.

◆ Research Categories: All.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, 12 projects relevant to breast cancer 

research were supported through the current PA and the previously issued PAs (PA-96-040 and PA-94-050).c

■ Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses (FLAIR) 

 (http://dtp.nci.nih.gov/branches/gcob/gcob_web17.html)

◆ Overview: Provides a flexible system within the SBIR and STTR programs to support the extensive needs of the 

complex drug and vaccine discovery and development process, from basic discovery through proof-of-principle 

demonstration in clinical trials.

◆ Research Categories: Biology; Treatment.

◆ Relevant Research Projects Resulting From This Initiative: Between 1998 and 2003, 14 projects relevant to breast 

cancer research were supported. Specific projects can be found in Appendix B, Table B33, by searching for the PA/

RFA numbers (PA-01-091, PAR-00-030, and RFA-CA-98-022).

■ Improve DNA, RNA and Protein Availability in Fixed Tissue (PAR-00-079)

◆ Overview: Supports the development of improved methods for fixing tissues and making nucleic acids and proteins 

more readily accessible from archived specimens.

◆ Research Categories: Biology; Etiology; Early Detection, Diagnosis, and Prognosis.

◆ Relevant Research Project Resulting From This PA: Between 1998 and 2003, two projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Tables B2, B13, and B32, by searching for 

the PA number.

■ In Vivo Cellular and Molecular Imaging Centers (ICMICs) (http://www3.cancer.gov/bip/ICMICs.htm)

◆ Overview: Facilitate interaction among scientists from a variety of fields to conduct multidisciplinary research on 

cellular and molecular imaging related to cancer.

◆ Research Categories: Biology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Resource Resulting From This Initiative: The NCI is currently supporting 7 ICMIC center grants and 12 

pre-ICMIC planning grants that provide time and funds for investigators and institutions to prepare themselves, 

organizationally and scientifically, to establish an ICMIC.

c. Lists of projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiatives Database.
October 2004 NCI Breast Cancer Progress Report

2-10 Chapter 2: Initiatives

■ Integrating Aging and Cancer Research (PA-02-169)

◆ Overview: Supports projects that expand the knowledge base on aging and age-related aspects of cancer in older 

persons. This initiative originated from a workshop entitled Exploring the Role of Cancer Centers for Integrating 

Aging and Cancer Research, which was organized by the National Institute on Aging and the NCI to provide a 

forum for leaders in cancer and aging research to express their views on pressing research needs.

◆ Research Categories: Biology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment; Cancer Control, 

Survivorship, and Outcomes.

◆ Relevant Resources Resulting From This PA: Reports from seven working groups address topics in Patterns of Care; 

Treatment Efficacy and Tolerance; Effects of Comorbidity on Cancer; Prevention, Risk Assessment, and Screening; 

Psychosocial Issues and Medical Effects; Palliative Care; End-of-Life Care and Pain Relief; and the Biology of Aging 

and Cancer.

■ Interdisciplinary Research Teams for Molecular Target Assessment (RFA-CA-00-001)

◆ Overview: Supports the development of methods to assess the effects of interventions directed at specific molecular 

targets that produce or are associated with the cancer phenotype.

◆ Research Categories: Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Research Projects Resulting From This RFA: Between 1998 and 2003, two projects relevant to breast 

cancer research were supported through this RFA.d

■ Minority-Based Community Clinical Oncology Program (MBCCOP) 

(http://www3.cancer.gov/prevention/ccop/mbccop.html)

◆ Overview: Supports a comprehensive clinical trials mechanism for disseminating the latest cancer prevention and 

treatment research findings to communities with large minority patient populations.

◆ Research Categories: Prevention; Treatment; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Program Resulting From This Initiative: The MBCCOP is composed of 13 funded groups of hospitals or 

private practices that participate in NCI-funded clinical trials.

■ Minority Institution/Cancer Center Partnership (MI/CCP) (http://minorityopportunities.nci.nih.gov/institutions/)

◆ Overview: Supports partnerships between Minority-Serving Institutions and NCI-designated Cancer Centers to 

increase training and involvement of scientists at minority institutions and to develop collaborative projects that 

address the disproportionate incidence and mortality rates of cancer in minority populations.

◆ Research Categories: All.

◆ Relevant Program Resulting From This Initiative: The MI/CCP emphasizes four target areas, including cancer 

research, research training and career development, cancer education, and cancer outreach. The MI/CCP offers three 

mechanisms of support for grantees:

Planning Grant for Minority-Institution/Cancer Center Collaborations (P20)

Cooperative Planning Grant for Comprehensive Minority Institution/Cancer Center Partnership (U56)

Comprehensive Minority Institution/Cancer Center Partnership (U54)

d. Lists of projects derived from initiatives can be found in the online Supplement to the Breast Cancer Progress Report: Initiatives Database.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-11

■ Molecular Target Drug Discovery for Cancer (PAR-01-045; PAR-01-046)

◆ Overview: Supports the identification of novel molecular targets, the validation of the target as a basis for cancer 

drug discovery, or the development of assays for target function.

◆ Research Categories: Biology; Etiology; Prevention; Treatment.

◆ Relevant Research Projects Resulting From These PAs: Between 1998 and 2003, 18 projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Tables B2, B5, B7, B9, B15, B17, B21, B30, 

B33, B36, and B29, by searching for the current PA numbers and the previously issued PA/RFA numbers (PAR-00-

060, PAR-00-061, PAR-00-062, and RFA-CA-00-002).

■ Mouse Models of Human Cancers Consortium (RFA-CA-04-002)

◆ Overview: Aims to derive, characterize, and validate mouse strains that model human cancers, including breast 

cancer, and to make these strains available to the research community. The Consortium infrastructure includes a 

Breast Cancer Models Working Group that fosters the development and use of mouse models serving as surrogate 

systems to study human breast cancer. Members of the Working Group are drawn from other NCI networks and 

consortia and the breast cancer research community, with participation by the Department of Defense and National 

Institute of Diabetes and Digestive and Kidney Diseases. The MMHCC convenes biannual meetings on progress in 

breast cancer modeling.

◆ Research Categories: Biology; Etiology; Prevention.

◆ Relevant Resources Resulting From This Initiative: Through the eMice Web site, researchers have access to mouse 

strains, reagents, analytical tools, protocols, gene data, drug databases, and other useful resources. There are 13 

strains of mice that model breast cancer or breast cancer metastasis that can be ordered from the NCI Mouse 

Repository for use in research.

■ NCI Center for Bioinformatics (NCICB) (http://ncicb.nci.nih.gov)

◆ Overview: Provides bioinformatics support and integrates diverse research initiatives.

◆ Research Categories: All.

◆ Relevant Resources Resulting From This Initiative: NCICB’s caCORE information management system software 

is available to researchers to facilitate their research needs. In 2003, NCICB introduced caBIG as an open-source 

public bioinformatics platform.

■ Nonmammalian Organisms as Models for Anticancer Drug Discovery (PAR-99-019; PAR-99-020)

◆ Overview: Supports projects that identify key genes, enzymatic activities, components of signaling pathways, or 

cellular processes that are altered in human cancer as potential intervention points that could be used in the design 

of new cancer drugs.

◆ Research Categories: Biology; Treatment.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, two projects relevant to breast cancer 

research were supported.e

■ Program for the Assessment of Clinical Cancer Tests (PACCT) (http://www.cancerdiagnosis.nci.nih.gov/assessment)

◆ Overview: Supports efforts to maximize the impact of cancer treatments and ensures the translation of new 

knowledge about cancer into clinical practice. A PACCT Strategy Group was convened to develop criteria for 

assessing which markers are ready for further development.

e. Lists of projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiatives Database.
October 2004 NCI Breast Cancer Progress Report

2-12 Chapter 2: Initiatives

◆ Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Programs Resulting From This Initiative: Several Web sites that help researchers gain access to human 

specimens: NCI Specimen Resource Locator, Shared Pathology Informatics Network, Tissue Array Research 

Program, and Tissue Expediter.

■ Shared Pathology Informatics Network (SPIN) (http://spin.nci.nih.gov/)

◆ Overview: Supports efforts to develop and use state-of-the-art informatics techniques to establish an Internet-based 

virtual database that will allow investigators from multiple institutions to locate appropriate human tissue specimens 

for their research.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Program Resulting From This Initiative: Software supplied by the SPIN initiative can be run at 

participating institutions and will be able to respond to researcher-initiated queries with a listing of pathology 

specimens and related data that meet the query criteria.

■ Shared Resources for Scientists Outside NCI Cancer Centers (PAR-99-127)

◆ Overview: Provides additional shared resource support to institutions that do not have NCI-funded Cancer Centers 

or Cancer Center planning grants.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Programs Resulting From This PA: Between 1998 and 2003, seven projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Table B33, by searching for the current PA 

number and the previously issued PA/RFA numbers (PAR-98-092 and RFA-CA-01-020).

■ Small Animal Imaging Resource Program (SAIRP) (http://www3.cancer.gov/dip/sairp.htm)

◆ Overview: Supports shared imaging resources to be used by cancer investigators and research related to small animal 

imaging technology.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Research Programs Resulting From This Initiative: Ten participating institutions provide imaging resources 

for investigators in their region of the United States.

■ Small Grants Program for Cancer Epidemiology (http://epi.grants.cancer.gov/ResPort/grants.html)

◆ Overview: Supports the formation of relationships between large research institutions and community-based 

programs and addresses cancer burden in minority communities.

◆ Research Categories: Biology; Etiology; Early Detection, Diagnosis, and Prognosis; Treatment; Cancer Control, 

Survivorship, and Outcomes.

◆ Relevant Programs Resulting From This Initiative: Between 1998 and 2003, 53 projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Tables B1, B7, B8, B10, and B11, by 

searching for the PA numbers (PAR-03-010, PA-01-021, PAR-98-023 and PAR-95-077).

■ Southern Community Cohort Study (SCCS) (http://www.southerncommunitystudy.org)

◆ Overview: Supports a large population-based research study that is examining the reasons African Americans are 

more likely to be affected by many cancers, including breast cancer.

◆ Research Categories: Etiology; Prevention; Cancer Control, Survivorship, and Outcomes.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-13

◆ Relevant Details of This Study: The SCCS will recruit about 70,000 African-American and 35,000 non-AfricanAmerican residents of the southern United States who will complete an interview and provide a DNA sample. 

Health outcomes in this group will be monitored for decades with the goal of identifying genetic factors that 

predispose certain groups to cancer.

■ Special Populations Networks (SPNs) (http://crchd.nci.nih.gov/spn/index.html)

◆ Overview: Supports collaborations between large research institutions and community-based programs to find ways 

of addressing important questions about the burden of cancer in minority communities.

◆ Research Categories: Prevention; Treatment; Cancer Control, Survivorship, and Outcomes.

◆ Relevant Programs Resulting From This Initiative: The current SPNs are composed of the following 18 projects in 

15 states across the United States:

American Indian Initiative in Arizona

Appalachia Cancer Network (ACN)

Arkansas Special Populations Access Network (ASPAN)

Asian American Network for Cancer Awareness, Research, and Training (AANCART)

Asian Tobacco Education and Cancer Awareness Research Initiative (ATECAR)

Cancer Awareness Network for Immigrant Minority Populations (CANIMP)

Deep South Network for Cancer Control

East Harlem Partnership for Cancer Awareness

Imi Halé, the Native Hawaiian Cancer Research and Training Network

Increasing Access to Clinical and Educational Studies (ACES)

Latin American Cancer Research Coalition (LACRC)

Latino/a Research and Policy Center

Maryland Special Populations Cancer Network

National Black Leadership-Cancer Control, Research and Training Network (NBL-CCRTN)

Pacific Islander Cancer Control Network (PICCN)

Redes En Acción

Special Populations Network for Cancer Control (SPNCC)

The Network for Cancer Control Research among American Indian and Alaska Native (AI/AN) Populations.

■ Specimen Resource Locator (http://pluto3.nci.nih.gov/tissue/default.htm)

◆ Overview: Enables researchers to locate human specimens for cancer research.

◆ Research Categories: Biology; Etiology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Program Resulting From This Initiative: The Specimen Resource Locator Web site provides investigators 

with information and automated tools for identifying tissue procurement systems, including those with samples 

from normal and diseased breasts.
October 2004 NCI Breast Cancer Progress Report

2-14 Chapter 2: Initiatives

■ Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors (RFA-CA-01-011)

◆ Overview: Supports the development of innovative technologies for the sensitive quantitation of the comprehensive 

spectrum of proteins present in human tissues.

◆ Research Categories: Biology; Early Detection, Diagnosis, and Prognosis.

◆ Relevant Research Project Resulting From This RFA: Between 1998 and 2003, one project relevant to breast cancer 

research was supported through this RFA:

Technology for Global and Quantitative Proteome Analysis

■ Therapeutic Modulation of Angiogenesis in Disease (PAR-98-096)

◆ Overview: Encourages the translation of basic knowledge of the angiogenic process into therapeutic applications.

◆ Research Categories: Biology; Prevention; Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, six projects relevant to breast cancer 

research were supported. Specific projects can be found in Appendix B, Tables B3, B15, and B16, by searching for 

the PA number.

■ Unconventional Innovations Program (UIP) (http://otir.cancer.gov/tech/uip.html)

◆ Overview: Supports the development of radically new technologies in cancer care that can transform what is now 

impossible into the realm of the possible for detecting, diagnosing, and intervening in cancer at its earliest stages of 

development.

◆ Research Categories: Early Detection, Diagnosis, and Prognosis; Treatment.

◆ Relevant Research Projects Resulting From This Initiative: A list of UIP-funded projects is available online and 

includes four projects with breast cancer relevance:

Molecular Imaging and Therapy of Solid Tumors With a Novel αvβ3-specific Nuclear Nanoparticle Targeted to the 

Neovasculature

Novel Technologies for Noninvasive Detection, Diagnosis, and Treatment of Cancer (a)

Novel Technologies for Noninvasive Detection, Diagnosis, and Treatment of Cancer (b)

Tissue Perfusion Imaging for Cancer Detection

Specialized Programs of Research Excellence (SPOREs)

In 1992, the NCI established the Specialized Programs of Research Excellence (SPOREs) to promote interdisciplinary research 

and to speed the bidirectional exchange of information between basic and clinical scientists. The SPORE program facilitates 

the translation of novel research ideas to the clinical care setting, with the goals of reducing cancer incidence and mortality, 

improving survival, and improving quality of life. Laboratory and clinical scientists work collaboratively to plan, design, 

and implement research programs that impact cancer prevention, detection, diagnosis, treatment, and control. In 2002 and 

2003, 32 clinical trials in breast cancer research were supported through the Breast Cancer SPOREs. Table 2-2 provides more 

information on the research projects, core resources, and training and other opportunities that are provided by the current 

Breast Cancer SPOREs.
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-15

Table 2-2. Breast SPOREs

Baylor College of Medicine

Projects:

■	Genetic Expression Profile of Taxotere Versus AC Sensitivity

■	Growth Factor and Stress Response Pathway in Endocrine Therapy Resistance

■	Molecular Classification and Prognostic Profiling of Ductal Carcinoma In Situ

■	Prevention of Breast Cancer Using Signal Transduction Inhibitors

■	Role of High-Frequency Hypersensitive Estrogen Receptor-Alpha Mutation in Breast Cancer Metastasis

Cores: Administrative Core, Biostatistics and Data Management, Pathology Core, and Tissue Core

Additional: Developmental Research Program and Career Development Program

Dana-Farber Cancer Institute

Projects:

■	Creation of Animal Models for Human Breast Cancer

■	Functional Testing for BRCA1 and BRCA2

■	Identification of Targets for Intervention in Breast Cancer

■	Molecular Markers in DCIS

■	Plasma Estrogens in Breast Cancer Risk and Prevention

■	Role of G2 Checkpoint Genes in Breast Cancer Susceptibility

Cores: Biostatistics Core, Clinical Data and Data Management Core, High-Risk Patients and Their Families, and Tissue 

and Pathology Core

Additional: Developmental Research Program and Career Development Program

Duke University Medical Center

Projects:

■ Application of Pharmacogenomics to Treatment of Breast Cancer

■ Genetic Modifiers of BRCA1 and BRCA2

■ Hypoxia and Chemoresistance in Breast Cancer

■ T-Helper Responses to Her2/neu in Breast Cancer Patients

Cores: Administration, Tissue Bank, Biostatistics and Informatics, and Molecular and Cell Technology

Additional: Developmental Research Program and Career Development Program
October 2004 NCI Breast Cancer Progress Report

2-16 Chapter 2: Initiatives

Georgetown University Medical Center

Projects:

■ A Phase III Multicenter Randomized Trial Comparing Cyclophosphamide, Thiotepa, and Carboplatin (STAMP V) 

With or Without IL-2-Activated Stem Cell Transplantation and Parenteral IL-2 for High-Risk Breast Cancer Patients

■ Antimetalloprotease Therapy

■ Development of Her-2/neu-Targeted Small Molecule Inhibitors as Novel Cancer Therapeutics

■ Inhibition of Breast Cancer Xenograft Tumor Growth by a Naturally Existing Secreted Form of VEGI (Vascular 

Endothelial Growth Inhibitor)

■ Mammary Carcinogenesis, the Role of Pleiotrophin

■ Resistance to Hormone and Chemotherapy in Breast Cancer

■ Systemic p53 Gene Therapy Markedly Enhances the Efficacy of Conventional Cancer Therapies

Cores: Breast Cancer Cell Line Resource, Breast Cancer Tumor Bank, SPORE Clinical Research Core, The Breast Cancer 

Serum Biomarker Resource, and Transgenic Shared Resource Core

Additional: Developmental Research Program and Career Development Program

Northwestern University Medical School

Projects:

■ Actions of Estrogen Agonists and Antagonists by Nonclassical Transcription Pathways

■ An Angiostatic Cocktail for Women With Refractory Breast Cancer: A Translational Study

■ Antiestrogens and Breast Density in Premenopausal Women

■ Drug Resistance to Antiestrogens

Cores: Administrative Core, Biostatistical Core, Clinical Core, and Tissue Resource Core

Additional: Developmental Research Program and Career Development Program

The Johns Hopkins University School of Medicine

Projects:

■ Molecular Detection of Breast Cancer

■ Molecular Epidemiology of Progression to Breast Cancer

■ Molecular Markers for Breast Cancer

■ Molecular Phenotypes of Breast Cancer

■ Novel Polyamine Analogues for Breast Cancer Treatment

■ Use of Modulators of DNA Methylation and Histone Deacetylation to Treat Breast Cancer

■ Vaccines: A New Paradigm for Breast Cancer

Cores: Administration and Communication Core, Biostatistics and Bioinformatics Core, and Human Specimen Resource 

and Database

Additional: Developmental Research Program and Career Development Program
NCI Breast Cancer Progress Report October 2004

Chapter 2: Initiatives 2-17

University of Alabama at Birmingham

Projects:

■ Biology and Intermediate Marker Role of a Novel Breast Cancer Oncogene, GKLF

■ Gene Therapy Specifically Directed at Tumor Vasculature

■ Molecular Regulation of Breast Cancer Metastasis

■ Polynucleotide Vaccine Therapy of Breast Cancer

■ Preclinical/Clinical Development of Novel Retinoids

■ Pretargeting Radioimmunotherapy of Metastatic Breast Cancer

Cores: Administrative Core, Biostatistical Core, Tissue Procurement Core, Immunopathology Core, and Clinical Trials 

Core

Additional: Developmental Research Program and Career Development Program

University of California, San Francisco

Projects:

■ A New Model System to Identify Markers for Risk and Targets for Chemoprevention

■ Breast Cancer Therapeutic Agents That Force Telomerase Misfunction

■ Identification and Targeting of Novel Breast Cancer Antigens for Antibody-Based Breast Cancer Therapy

■ Molecular Determinants of Response to RTK Pathway Inhibitors

■ Predictors of Recurrence in Women with DCIS

■ Targeted Drug Delivery via Immunoliposome Technology

Cores: Administrative Core, Advocacy Core, Preclinical Animal Core, and Tissue-Outcomes Core

Additional: Developmental Research Program and Career Development Program

University of North Carolina at Chapel Hill 

Projects:

■ A Novel Chemotherapy Combination for Breast Cancer

■ Breast Tumor Molecular “Profiling” Using cDNA Microarrays

■ Carolina Breast Cancer Study: DNA Repair Genes and Breast Cancer Risk

■ Carolina Breast Cancer Study: ER Alterations in Breast Cancer Development

■ Correlation of Molecular Markers With Response to Neoadjuvant Chemotherapy

■ Enhancing a Breast Cancer Vaccine

■ Inhibition of Chemotherapy-Induced NFB

Cores: Administrative Core, Biostatistics and Bioinformatics Core, Genomics and Microarray Core, Molecular Analysis 

and High-Throughput Genotyping Core, and Tissue Procurement and Analysis Core

Additional: Developmental Research Program and Career Development Program
October 2004 NCI Breast Cancer Progress Report

2-18 Chapter 2: Initiatives

Vanderbilt University

Projects:

■ HER (erbB) Tyrosine Kinase Inhibitors in Treatment-Naïve, Operable Breast Cancer

■ Molecular Epidemiology of Proliferative Breast Disease

■ Molecular Imaging of Breast Carcinoma and Therapeutic Response

■ Predictive Markers of Clinical Response to Paclitaxel Therapy in Stage II/III Breast Cancer

Cores: Administrative Core, Antibody Production and Characterization Core, Biomedical Informatics Core, Biostatistics 

Core, Proteomics and Emerging Technologies Core, and Tissue Core

Additional: Developmental Research Program and Career Development Program

Ongoing NCI Research: SPOREs

Developmental Projects in Early Detection and Drug Targeting

The SPORE Working Group on Biomarker Development recognizes the importance of pursuing research on novel biomarkers 

for potential clinical applications. This group recently identified the KLF4 Biomarker Project, currently under way at the 

University of Alabama (UAB), as an important area for future development. Researchers involved with this project are testing 

the hypothesis that nuclear localization of the Krüppel-like transcription factor (KLF4) protein identifies an aggressive subset 

of early-stage breast cancers. Previous studies have demonstrated that KLF4 is upregulated in breast cancer and squamous 

cell carcinomas of the oral cavity and skin (Foster et al., 2000). In their first study of 146 patients, researchers demonstrated 

that the KLF4 marker is an independent prognostic factor that is more strongly associated with an outcome than any other 

biomarker assessed in parallel (p53, ER/PR, p27Kip1, EGFR, Ki67, Bcl-2, and Her2/neu) (Pandya et al., 2004). Results from 

this initial study suggest that KLF4 could be used to identify approximately one-half of early-stage breast cancer patients who 

will eventually die of the disease.

The SPORE Molecular Targets Working Group identified the Immunoliposome Project at the University of California, San 

Francisco (UCSF) Breast Cancer SPORE site as an important project. Scientists at this site are working on advanced drug 

delivery technologies that enable highly robust and versatile encapsulation of various cytotoxic compounds into stabilized 

liposomes. Novel liposome constructs containing existing chemotherapeutic drugs vinorelbine, vincristine, epirubicin, and 

campothecins result in extremely stable and long-circulating nanoparticles. The antitumor activity of liposome-encapsulated 

drugs can be enhanced by the addition of an immunoconjugate, which allows for antigen-specific targeting of the liposome. 

The UCSF Breast Cancer SPORE project has developed immunoliposomes (ILs) directed against HER2 and has demonstrated 

their effectiveness in delivering doxorubicin for enhanced in vivo antitumor activity (Park et al, 2002). HER2-targeted ILs 

containing doxorubicin have been optimized for clinical development and are currently being manufactured by industry 

partners for use in clinical studies.

Collaborations and Partnerships

Breast Cancer SPOREs meet annually at a SPORE Investigators Workshop to share data, assess research progress, and identify 

new research opportunities. In many cases, funded SPORE institutions forge collaborations with each other and with clinical 

trials groups to increase the likelihood of success for their projects. For example, the University of California, San Francisco Bay 

Area Cancer Translational Research Program, the University of North Carolina at Chapel Hill Breast Cancer SPORE, and the 

Georgetown University SPORE share funding to study the use of magnetic resonance imaging (MRI) as a quantitative tool to 

measure response to chemotherapy in Stage III breast cancer patients and to correlate these findings with biomarker analyses 

performed on tumor biopsies. The study entitled Stage III MRI and Correlative Science Companion Study is led by UCSF 

and includes collaborations at SPORE institutions, centers that do not have Breast Cancer SPORE funding (the Memorial 
Report of the Breast Cancer Progress Review Group October 2004

Chapter 2: Initiatives 2-19

Sloan-Kettering Cancer Center, the University of Texas Southwestern Medical Center, and the University of Pennsylvania 

Cancer Center), and other NCI-sponsored groups (the Cancer and Leukemia Group B [CALGB] and the American College 

of Radiology Imaging Network [ACRIN]). The SPORE program supports the correlative science component of the project 

while the MRI analyses and clinical trials are supported by ACRIN and CALGB, respectively. The inclusion of this many 

collaborating institutions ensures the accrual of sufficient numbers of patients for solid statistical analysis of the study’s 

endpoints, which include the identification of new, early predictors of response and the establishment of a direct relationship 

between imaging/marker findings and survival.

In another example of a unique collaboration, the Avon Foundation (AVON) and NCI developed the AVON-NCI Progress 

for Patients (PFP) Awards Program, a special private-public partnership to fund innovative research for preventing, detecting, 

diagnosing, and treating breast cancer. AVON pledged $20 million to fund breast cancer research over 5 years through a 

limited competition involving institutions with NCI-funded SPORE grants and Cancer Center grants. The program goal is to 

increase the number of new early-phase clinical breast cancer interventions and help move promising drugs, biomarkers, and 

procedures into Phase III clinical trials. By the end of 2003, eight SPORE projects in breast cancer had received supplemental 

funding through the PFP Awards mechanism. The following ongoing research projects address issues relevant to breast cancer 

prevention, treatment, and early detection/diagnosis/prognosis:

■ Antiangiogenic Therapies for Breast Cancer

■ Biological Markers in Breast Cancer Treated by Neoadjuvant Chemotherapy

■ Markers of Short-Term Breast Cancer Risk in Fine-Needle Aspiration

■ New Biomarkers for Aromatase Inhibitor Therapy

■ Novel Approaches for Patients With Large Breast Cancers

■ Response to Preoperative Therapy in Breast Cancer

■ Surrogate Endpoints in Prevention Studies and Ductal Lavage

■ Validation of Breast Biomarker Panel

These types of collaborations and partnerships increase the likelihood of success for SPORE researchers in their efforts to 

translate basic laboratory findings into practical clinical applications for treating breast cancer.

NCI-Supported Research Referenced in Chapter 2

Foster KW, Frost AR, McKie-Bell P, Lin CY, Engler JA, Grizzle WE, Ruppert JM. Increase of GKLF messenger RNA and 

protein expression during progression of breast cancer. Cancer Res. 2000 Nov 15;60(22):6488-6495.

Pandya AY, Talley LI, Frost AR, Fitzgerald TJ, Trivedi V, Chakravarthy M, Chhieng DC, Grizzle WE, Engler JA, Krontiras 

H, Bland KI, LoBuglio AF, Lobo-Ruppert SM, Ruppert JM. Nuclear localization of KLF4 is associated with an aggressive 

phenotype in early-stage breast cancer. Clin Cancer Res. 2004 Apr 15;10(8):2709-2719.

Park JW, Hong K, Kirpotin DB, Colbern G, Shalaby R, Baselga J, Shao Y, Nielsen UB, Marks JD, Moore D, Papahadjopoulos 

D, Benz CC. Anti-HER2 immunoliposomes: Enhanced efficacy attributable to targeted delivery. Clin Cancer Res. 2002 

Apr;8(4):1172-1181.

NCI Breast Cancer Progress Report October 2004

Chapter 3: Biology 3-1

Chapter 3:

Breast Cancer Biology: NCI’s Investment and 

Recent Progress

Given that the two clinical challenges in breast cancer research are to prevent the onset of disease and to 

effectively treat metastatic disease, the overarching basic biological questions that need to be answered 

involve understanding the normal and early malignant biology of the mammary gland, and identifying 

factors responsible for metastatic disease. Charting the Course: Priorities for Breast Cancer Research

Basic biology research is fundamentally important for the advancement of many areas of cancer research, as it provides the 

foundation on which applied studies in early detection, diagnosis, prevention, and treatment are built. In its 1998 report, the 

Breast Cancer PRG outlined three overarching themes in breast cancer biology research that required specific attention in the 

coming years: the need to elucidate the normal biology of the mammary gland, the process of malignant transformation in 

the breast, and mechanisms of breast cancer metastasis. Within these three priority areas, the PRG identified more than 20 

subpriorities that could be used to guide the research community in its efforts to understand the basic biology of breast cancer.

In the years since the PRG report, the NCI has generated specific initiatives, Program Announcements and Requests for 

Applications aimed at addressing the PRG’s priorities. Research conducted in response to these efforts, in addition to the broad 

range of investigator-initiated biology research, has been fruitful, yielding results in breast cancer biology that have fueled 

progress in other areas of breast cancer research. Significant progress has been made in understanding the biology of mammary 

stem cells, genetic changes that occur during breast cancer development and metastasis, mechanisms by which tumorsuppressor genes (e.g., BRCA1 and BRCA2) function, and nuclear hormone receptor function.

New mouse models of breast cancer have been generated that closely mimic the different types of breast cancer found in 

humans. Models such as the BRCA1-null mouse and the Her2/neu transgenic mouse have been useful for understanding the 

biology of estrogen receptor (ER)-negative breast tumors, which are the most difficult to treat.

The information gleaned from these and other biology projects have contributed to progress in the areas of breast cancer 

prevention, detection, diagnosis, and treatment. For a more comprehensive understanding of this progress, readers are urged 

to see Chapters 5, 6, and 7 of this report. In addition, basic biology research both influences and is influenced by etiologic 

research on genetics and biological mechanisms of cancer development and progression. Examples of progress can be found in 

this chapter and Chapter 4.

NCI’s Investment and 

Response

From FY1998 to 2003, NCI’s extramural investment 

in research on breast cancer biology has increased from 

$43.2 million to $86 million (Figure 3-1). This increase 

in funding corresponds to increases in the number of 

projects that are responsive to PRG priorities in biology. 

Table 3-1 summarizes the NCI’s responsiveness to the 

three Breast Cancer PRG research priorities for biology 

and the genetics priorities relevant to biology.1

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars

Figure 3-1. NCI’s extramural investment in breast cancer 

biology research: 1998-2003 (in millions of dollars)

1 A project may map to more than one PRG priority and therefore be represented in more than one figure. Projects active in 2003 are listed in Appendix B (Tables B-1 to B6) by the Principal Investigator’s name for each PRG priority.
October 2004 NCI Breast Cancer Progress Report

3-2 Chapter 3: Biology

Table 3-1. NCI Efforts Responsive to PRG Priorities and Opportunities in Biologya

PRG Priority:

What are the genetic and biological bases of 

mammary gland development throughout the life of 

the organism?b

NCI Efforts:

■ The original PRG indicated six subpriorities to this 

priority, which addressed the following topics:

◆ The nature of mammary gland stem cells

◆ Principal cell types involved in mammary 

development

◆ Control of growth, death, and differentiation during mammary development

◆ Critical transcriptional regulatory mechanisms in mammary development, including steroid receptor coactivators 

and corepressors

◆ Principal signaling molecules and pathways in mammary gland development

◆ Principal cell cycle checkpoints and their controls in mammary development

■ In FY2003, examples of active areas of investigation included vitamin D-mediated apoptosis in mammary cells, 

prolactin interactions in mammary gland development and tumorigenesis, biology of mammary gland development 

and tumorigenesis, and in vivo cell growth control mediated by C/EBP-β and C/EBP-delta.

■ On October 2-3, 2002, NCI sponsored a conference on Laser Capture Microdissection and Macromolecular Analysis of 

Normal Development and Pathology. On July 19-20, 2001, NCI sponsored the Breast Cancer Think Tank: Mammary 

Gland Biology Seminar Series to discuss mammary gland biology with the NCI research community.

■ NCI initiatives addressing this priority included the Cancer Genome Anatomy Project (CGAP), Complex Formation 

in Hormonal Regulation of Gene Expression, Cooperative Human Tissue Network (CHTN), and Mammalian Gene 

Collection.

PRG Priority:

What are the genetic and epigenetic bases of pathologic lesions that occur during the progression of breast cancer from 

the earliest hyperplasias to invasive disease?c (Biology-B)

Identify somatic mutations and epigenetic alterations that are due to exogenous factors or to chance. As these are 

detected, it will be important to know which ones are rate limiting. Once rate-limiting changes are identified, specific 

pathways altered by these genetic events can provide clues to possible targets for: (1) identifying very small lesions 

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

a. Some of the original PRG priorities are addressed jointly in Table 3-1 because these priorities address partially overlapping issues and they are relevant to many of 

the same research projects and initiatives.

b. This priority merges the two original PRG priorities: “What are the genetic and biological bases of mammary gland development?” from the Biology section and 

“Characterize genetic and expression profiles for normal breast epithelium at birth, puberty, adult, pregnancy, lactation, regression, and menopause” from the 

Genetics section.

c. This priority merges the two original PRG priorities “What are the genetic and epigenetic bases of pathologic lesions that occur during the progression of breast 

cancer from the earliest hyperplasias to invasive disease; can we develop appropriate diagnostic markers based on these studies?” from the Biology section and 

“Characterize genetic and expression profiles of breast abnormalities at progressive stages of development from normal to invasive disease” from the Genetics section.
NCI Breast Cancer Progress Report October 2004

Chapter 3: Biology 3-3

(diagnosis); (2) treatment (by reversing the 

altered phenotype); (3) identifying tumor cells (to 

individualize therapy based on tumor genotype); 

and (4) prevention (by systemic treatment of women 

before critical changes occur).d (Genetics-B)

NCI Efforts:

■ The original PRG indicated eight subpriorities 

for the Biology-B priority, which addressed the 

following topics:

◆ Critical signaling pathways in tumor progression

◆ The mechanism by which genetic and genomic 

instabilities are triggered during tumor progression

◆ Critical transcriptional regulatory mechanisms in mammary development, including steroid receptor coactivators 

and corepressors

◆ The bases of stem cell-carcinogen interactions

◆ Epithelial and stromal cell interactions that are important in tumor cell progression

◆ The nature of checkpoint abrogation mechanisms in tumor progression

◆ The relative roles of estrogen receptor (ER)-α and ER-β in tumor progression

◆ The importance of immune tolerance in tumor progression

■ In FY2003, examples of active areas of investigation relevant to the following priorities included:

◆ Biology-B: Calmodulin and ER function, role of Her4 as a differentiation factor in breast cancer, role of the tumor 

suppressor LIBC in inflammatory breast cancer phenotype, the structural basis for ER-β receptor activation, actinregulated apoptosis in mammary tumorigenesis, molecular alterations in premalignant and in situ breast lesions, 

TGF-β receptor and tumor progression, and identification of allele variant genes that are risk factors for human 

breast cancer.

◆ Genetics-B: Accelerated senescence in tumor cells, a novel HOX gene target in breast cancer, DNA 

hypermethylation in breast cancer, gene expression signatures of early breast cancer, identification of M5CpG 

alterations in breast carcinomas, and identification of chromosomal aberrations in human epithelial cancers and 

hematological malignancies and their respective murine model systems (comparative cancer cytogenetics).

■ On October 17-21, 2001, NCI and the American Association for Cancer Research sponsored a special conference, 

Cancer and Chromosomal Organization and Epigenetics of Cancer. On July 19-20, 1999, NCI sponsored the workshop 

DES Research Update 1999: Current Knowledge, Future Directions to address the status of biological, epidemiological, 

clinical, and education/outreach research on diethylstilbestrol (DES).

NCI initiatives addressing this priority included Applications of Innovative Technologies for the Molecular Analysis of 

Cancer, Cancer Molecular Analysis Project (CMAP), Cooperative Human Tissue Network (CHTN), Cooperative Breast 

Cancer Tissue Resource (CBCTR), Director’s Challenge: Toward a Molecular Classification of Tumors, and Mouse 

Models of Human Cancers Consortium.

0

100

200

300

400

500

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

Biology-B Genetics-B

d. This priority was part of the Genetics section in the original Breast Cancer PRG report.
October 2004 NCI Breast Cancer Progress Report

3-4 Chapter 3: Biology

PRG Priority:

What are the molecular, genetic, and cellular 

bases of the biological processes involved 

in metastasis? Can we develop appropriate 

diagnostic markers based on these studies?

NCI Efforts:

■ The original PRG indicated nine 

subpriorities to this priority, which 

addressed the following topics:

◆ Cell survival pathways operant in 

metastasis

◆ Regulation of tumor angiogenesis

◆ Interaction of metastatic cells with bone

◆ Control of proteolysis in metastasis

◆ Tumor cell motility mechanisms operant in metastasis

◆ Importance of epithelial-stromal interactions in metastasis

◆ Important signaling pathways in metastasis

◆ Cell-cycle checkpoint abrogation mechanisms operant in metastatic cancers that render them more refractory to 

systemic treatment

◆ Aspects of tumor cell physiology of established and metastatic cancers that render them more refractory to systemic 

treatments

■ In FY2003, examples of active areas of investigation included antiestrogenic effects on tumor angiogenesis, a novel 

function for vascular epithelial growth factor (VEGF) in breast carcinoma survival, biology of VEGFs in the mammary 

gland, molecular mechanism of tumor-osteoclast interactions, imaging lymphatic clearance in tumor metastasis, effect 

of obesity on mammary tumorigenesis and metastasis, molecular analysis of breast cancer metastasis to the brain, and 

molecular biology of the metastatic phenotype.

■ On April 25-27, 2002, NCI sponsored the 3rd North American Symposium on Skeletal Complications of Malignancy.

■ NCI initiatives addressing this priority included The Director’s Challenge: Toward a Molecular Classification of 

Tumors, Molecular and Cellular Biology of Metastatic Tumor Cells, Mouse Models of Human Cancers Consortium, 

and Technologies for Comprehensive, 

Sensitive, and Quantitative Protein Analysis in 

Human Tumors.

PRG Priority:

Identify and clone the remaining major 

predisposing genes.e

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

e. This priority was part of the Genetics section in the original 

Breast Cancer PRG report.
NCI Breast Cancer Progress Report October 2004

Chapter 3: Biology 3-5

NCI Efforts:

■ In FY2003, examples of active areas of investigation included functional analysis of BRCA1, Protein Kinase C as a 

marker in tamoxifen-resistant breast cancer, the genetics and epigenetics of cancer, identification of allele variant genes 

that are risk factors for human breast cancer, and the interaction of genes with risk behaviors such as smoking in breast 

cancer etiology.

■ NCI initiatives addressing this priority included the Cancer Genome Anatomy Project (CGAP), Mammalian Gene 

Collection, and Specimen Resource Locator.

PRG Priority:

Use experimental model systems to determine 

the effects of mutant genes on the mammary 

gland, ovary, and endometrium.f

NCI Efforts:

■ In FY2003, examples of active areas 

of investigation included use of an 

ER-negative transgenic rat mammary 

model overexpressing neu to study 

chemoprevention; transgenic models 

for prostate and breast cancer; functional analysis of breast cancer susceptibility genes in mice; identification of 

chromosomal aberrations in human epithelial cancers, hematological malignancies, and their respective murine model 

systems; and genetic modifiers of initiation and progression of mammary cancer.

■ NCI initiatives addressing this priority included the Molecular and Cellular Biology of Metastatic Tumor Cells, Mouse 

Models of Human Cancers Consortium, and Stages of Breast Development: Normal to Metastatic Disease.

Additional Breast Cancer Biology Projects:

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the role of the 

prohibitin protein in mediating breast cancer 

suppression; the Cooperative Breast Cancer 

Tissue Resource; function of steroid receptors 

in subcellular compartments; in vivo imaging 

analysis of steroid/nuclear receptor function, 

tumor oxygenation, vascularization, and radio 

response; regulation of the sodium/iodide 

symporter in the breast; and structure of 

mammary tumor MAT8 and the FXYD proteins.

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

f. This priority was part of the Genetics section in the original Breast Cancer PRG report and modified from the original “Carry out experimental human genetics 

in mice, by generating mice with both wild-type and mutant human genes. Determine the effects of these genes on mammary gland, ovary, and endometrium 

(recognizing mouse-human differences). Determine the effects of mutations against different genetic backgrounds, with the goal of identifying genetic modifiers 

of mutant alleles.”
October 2004 NCI Breast Cancer Progress Report

3-6 Chapter 3: Biology

The NCI has responded to the PRG priorities and recommendations in breast cancer biology by expanding its investment in 

initiatives relevant to this specific research category. Initiatives that directly impacted breast cancer biology research during the 

years 1998 to 2003 are described in Table 3-2. In addition to these category-specific initiatives, some initiatives are relevant 

to many aspects of breast cancer research, including biology. The following list of broadly applicable initiatives is described in 

detail in Table 2-1:

■ Aging Women and Breast Cancer

■ Applications of Innovative Technologies for the Molecular Analysis of Cancer

■ Bioengineering Research Partnerships

■ Breast Cancer Faculty

■ Cancer Biomedical Informatics Grid (caBIG)

■ Cancer Centers Program

■ Cancer Genome Anatomy Project (CGAP) 

■ Cancer Imaging Program (CIP) 

■ Cancer Molecular Analysis Project (CMAP) 

■ Cancer Research Small Grant Program

■ Cancer Research Training, Career Development, and Education Opportunities 

■ Competing Supplements for Organotypic Models of Cancer

■ Cooperative Breast Cancer Tissue Resource (CBCTR)

■ Cooperative Human Tissue Network (CHTN)

■ Director’s Challenge: Toward a Molecular Classification of Tumors

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

■ Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses (FLAIR)

■ Improving DNA, RNA, and Protein Availability in Fixed Tissue 

■ Insight Awards to Stamp Out Breast Cancer

■ Integrating Aging and Cancer Research

■ In Vivo Cellular and Molecular Imaging Centers (ICMICs) 

■ Minority Institution/Cancer Center Partnership (MI/CCP)

■ Molecular Target Drug Discovery for Cancer

■ Mouse Models of Human Cancers Consortium

■ NCI Center for Bioinformatics

■ Nonmammalian Organisms as Models for Anticancer Drug Discovery

■ Shared Pathology Informatics Network (SPIN)

■ Shared Resources for Scientists Outside NCI Cancer Centers

■ Small Animal Imaging Resource Program (SAIRP)

■ Small Grants Program for Cancer Epidemiology
NCI Breast Cancer Progress Report October 2004

Chapter 3: Biology 3-7

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer

■ Specimen Resource Locator 

■ Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors

■ Therapeutic Modulation of Angiogenesis in Disease

Table 3-2. NCI Initiatives Relevant to Breast Cancer Research: Biologya

Initiatives Focused on Breast Cancer Research

■ Stages of Breast Development: Normal to Metastatic Disease (PA-99-162)

◆ Overview: Supports the study of the molecular, cellular, endocrine, and other physiological influences on the 

development and maturation of the normal mammary gland and alterations involved in early malignant and 

metastatic breast cancer.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, 25 projects relevant to breast cancer research 

were supported through this PA. Specific projects can be found in Appendix B, Tables B1-B5, B7, B9, B11, B14, 

B19, B30, and B33, by searching for the PA number.

Initiatives With Breast Cancer-Relevant Components

■ Bioengineering Nanotechnology Initiative (PA-02-125)

◆ Overview: Supports projects on nanotechnology that are potentially useful to biomedicine.

◆ Relevant Projects Resulting From This PA: Pending—this PA will remain open until June 3, 2005.

■ Complex Formation in Hormonal Regulation of Gene Expression (PA-02-100)

◆ Overview: Supports research addressing the role of nuclear hormone receptor complex formation in hormonal 

regulation of gene expression.

◆ Relevant Projects Resulting From This PA: Pending—this PA will remain open until May 1, 2005.

■ Mammalian Gene Collection (MGC) (http://mgc.nci.nih.gov/Info/Summary)

◆ Overview: A trans-NIH initiative that provides full-length open-reading-frame (FL-ORF) clones for human, mouse, 

and rat genes.

◆ Relevant Results From This Initiative: The MGC has sequenced and verified the complete FL-ORFs for a 

nonredundant set of 11,666 human genes, 18 of which are breast cancer-specific.

■ Molecular and Cellular Biology of Metastatic Tumor Cells (PA-01-020)

◆ Objective: Supports the study of molecular and cellular biology of metastatic tumor cells through collaborations that 

facilitate scientific interchange between investigators with experience in the biology of metastasis and others with 

more basic scientific disciplines such as molecular biology, cellular biology, andbiochemistry.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, 15 projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B24 and B32, by 

searching for the current PA number and the previously issued PA numbers (PA-98-029 and PA-93-016).

a. Lists of the projects derived from each initiative can be located in the online Supplement to the Breast Cancer Progress Report: Initiative Database.
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3-8 Chapter 3: Biology

■ Molecular Interactions Between Tumor Cells and Bone (RFA-CA-03-013)

◆ Overview: Supports studies that delineate the role of bone microenvironment on tumor cell survival and 

colonization. Collaborative interactions among bone biologists, clinical oncologists, and cancer biologists are 

highly encouraged. These studies contribute toward a better understanding of the molecular events that account for 

homing of tumor cells to the bone and lead to the generation of novel therapeutic reagents.

◆ Relevant Projects Resulting From This RFA: Between 1998 and 2003, three projects relevant to breast cancer 

research were supported through this RFA. Specific projects can be found in Appendix B, Tables B3 and B33, by 

searching for the current RFA number.

■ Structural Biology of Membrane Proteins (PA-02-108 , PA-02-060)

◆ Overview: Supports research leading to the solution of membrane protein structures at atomic resolution, with 

specific emphasis on membrane proteins and complexes associated with the biology, diagnosis, and treatment of 

cancer.

◆ Relevant Projects Resulting From These PAs: Between 1998 and 2003, one project relevant to breast cancer research 

was supported through the previously issued PA (PA-99-004): Structure of Mammary Tumor MAT8 and the FXYD 

Proteins.

Ongoing NCI Research: Recent Progress in Breast Cancer 

Biology

Mammary Gland Development and Breast Cancer Susceptibility

NCI-supported studies on the basic biology of breast cancer have led to considerable progress toward defining and 

characterizing the cells and genes that contribute to breast cancer susceptibility, initiation, and establishment. One especially 

active area focuses on the question of whether breast cancer heterogeneity results from different cells of origin undergoing 

discrete and different initiating events, alternate pathways of carcinogenesis from a single kind of cancer progenitor, or 

a combination—i.e., a limited set of progenitors and several common pathways acting in concert—that results in the 

heterogeneous tumor types that are observed. The answers from studies in a variety of in vitro and in vivo human and rodent 

model systems indicate that breast cancer heterogeneity is due to this last mechanism.

Studies of the hematopoietic system and its malignancies clearly demonstrate that there are stem and progenitor cell 

populations with differing properties that are targets for oncogenesis. Stem cells in adult tissues are able to divide to renew 

themselves as well as to differentiate into the cell lineages that are needed for normal function of a particular tissue or organ 

(Weissman et al., 2001). Mammary gland epithelial stem cells possess a high capacity to reproduce themselves, as well as the 

developmental ability to produce lineage-committed ductal and alveolar cells in the breast, and recent work established that an 

entire functional mammary gland can be generated from these stem cells (Kordon and Smith, 1998). Mammary stem cells are 

thought to be essential for the normal growth and differentiation of the mammary gland during puberty, pregnancy, lactation, 

and involution. Unlike other adult tissues and organs, which have an established morphology, mammary gland architecture 

undergoes substantial change during these processes.

During the involution process that follows weaning and cessation of lactation, the majority of mammary alveolar cells undergo 

apoptosis, with the exception of a unique population of epithelial stem cells that appears to undergo expansion at this time. 

This expanding population of cells increases in size with each subsequent pregnancy. This distinctive population is not present 

in the nulliparous mammary gland; thus, these cells are hypothesized to contribute to the tumorigenesis resistance mechanism 

displayed by multiparous women (Wagner et al., 2002). There are several experimental rodent models that point to the p53

tumor suppressor as a key player in the process of hormone-induced protection (Medina and Kittrell, 2003; Medina, 2004).
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Chapter 3: Biology 3-9

Although the concept of breast cancer stem cells is not new, only recently have researchers identified putative stem cells in the 

mammary gland and demonstrated their role in the development of breast cancer. In a landmark experiment, these rare breast 

cancer-initiating cells were identified in a population of human mammary tumor cells injected into immunocompromised mice 

(Al-Hajj et al., 2003). These transformed stem cells are able to give rise to heterogeneous mammary tumors and likely represent 

the only known population of tumor cells with the capability of initiating tumor growth. These findings have important 

therapeutic ramifications and shed light on the mechanism by which the induction of premature stem cell senescence reduces 

the risk of mammary cancer (Boulanger and Smith, 2001).

One particularly important issue for choice of therapy and long-term prognosis is the stem/progenitor cell origin of the 

breast tumors that are ERα-negative versus ERα-positive; the former are more aggressive, less responsive to therapy, and far 

more likely to recur. One hypothesis is that the mammary gland self-renewing stem cell is ERα-negative, and in response 

to differentiation conditions, ERα-positive progenitors arise that continue to self-replicate or differentiate. The ERαnegative stem cell can also give rise via the same or different mutations to ERα-negative cancer stem cell populations with 

different properties. Subsequent stochastic changes give rise to a number of subsets of breast cancer with differing degrees of 

aggressiveness and clinical course (Dontu et al., 2004). These hypotheses will require further testing.

The capacity now exists to test these stem/progenitor questions with a variety of model systems. NCI-funded investigators 

identified a mammary epithelial cell population with several stem/progenitor cell qualities, including expression of stem cell 

antigen-1 (Sca-1). These markers are useful for both the isolation of functional mammary epithelial stem/progenitor cells 

and the analysis of tumor etiology and phenotype in genetically engineered mouse models (Welm et al., 2002). Transgenic 

expression of the Wnt-1 proto-oncogene in the mouse mammary gland causes expansion of epithelial cells that express 

progenitor cell markers keratin 6 and Sca-1. The resulting tumors express these markers and contain at least two populations 

of tumor cells—epithelial cells and myoepithelial cells—which implies that they arose by differentiation from an oncogenic 

progenitor cell. These results suggest that mammary stem and/or progenitor cells may be targets for oncogenesis by Wnt1. Mammary tumors arising in transgenic mice that express β-catenin and c-Myc, which both encode proteins in the same 

pathway as Wnt-1, also have a significant proportion of myoepithelial cells and cells expressing keratin 6; however, mammary 

tumors from transgenic mice that express neu, H-Ras, or polyoma middle T-antigen contain very few myoepithelial cells or cells 

expressing markers of progenitor cells. These data suggest that the heterogeneity of tumors in mouse breast cancer models may 

partially reflect the selection or expansion of different progenitors (Li, Welm, et al., 2003).

Another model that mimics the natural history of a subset of human breast cancer is a p53-null mouse that is made in 

a particular strain background (BALBc). The p53-null normal mammary epithelium is as dependent on estrogen and 

progesterone for growth as p53+ epithelium. However, estrogen and progesterone, singly or together, strongly stimulate 

mammary gland tumorigenesis only in the p53-null mouse (Medina et al., 2003). The hormonally transformed ERα-positive 

cells are serially transplanted into cleared fat pads of p53+ mice. The tumors that grow out are often ERα-negative, and 

serial transplantation of cells from these tumors in ovariectomized p53+ mice leads to the development of aggressive tumors, 

demonstrating that ovarian hormones are no longer required for tumorigenesis. This model should prove valuable for testing 

chemopreventive agents against either ERα-negative or ERα-positive tumors. This transplantation model is complemented by 

a p53-mutant transgenic mouse model (Lin et al., 2004) in which the activity of p53 is lost specifically in the mammary gland. 

The natural history of mammary cancer in this line simulates the transition from ERα-positive to ERα-negative, and both 

liver and lung metastases are observed. In addition, genetic alterations that accompany human breast cancer progression, such 

as amplification of c-Myc and activation of Her2/neu/erbB2, are also reproduced in this model. Effective models of human 

breast cancer that address defective BRCA1 or BRCA2 can be found in rodents other than mice. Using a very clever technique 

to screen through the many progeny resulting from germline mutagenesis, a group of investigators was able to identify rat 

strains that have mutations specifically in these two susceptibility genes (Zan et al., 2003). The rats are being followed for the 

development of mammary cancer and possible ovarian epithelial cancer.

Due to the multigenic nature of breast cancer, finding all of the genes involved using human population studies is a daunting 

task. Particularly challenging is the fact that while most susceptibility genes are common, each one has a low penetrance in the 

general population, which means that many genes probably contribute to susceptibility or resistance. The use of comparative 

genomics in model systems is increasingly valuable for finding these cooperating alleles. Two studies have used congenic rats to 
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3-10 Chapter 3: Biology

refine the location of two of the eight susceptibility regions previously identified (Samuelson et al., 2003; Haag et al., 2003). 

Further refinement is under way to enable isolation of the relevant genes and evaluation of their role in human breast cancer 

susceptibility. Another research group used a clever strategy that combines the facile genetics of inbred mice and the growing 

collection of human and mouse SNPs. They substantially narrowed the location of a common susceptibility locus in mice 

and then searched through SNPs in the human genes in the corresponding human chromosome location to verify the STK15 

gene, which encodes the Aurora kinase, as a low-penetrance susceptibility gene in breast cancer. Subsequent studies have shown 

that this same allelic variant has a role in other common human epithelial cancers (Ewart-Toland et al., 2003). The Aurora 

kinases normally function to maintain chromosome integrity; if they are overexpressed, they acquire oncogenic properties, 

causing centrosome amplification, transformation, and aneuploidy. A recent study showed that overexpression of Aurora A 

kinase is a very early event in rat mammary carcinogenesis (Goepfert et al., 2002); the consistency of the observation regarding 

centrosome irregularities in a number of human cancers has prompted the development of an Aurora kinase inhibitor that is 

now in clinical trials.

A number of publications describe innovative new multicell systems to study the interactions of human breast cancer 

epithelial cells with other cells in the tissue environment. In one case, hydrated collagen gel was used to support studies of 

the interactions between myoepithelial cells and luminal epithelial cells, and between tumor cells and peritumoral fibroblasts. 

From these studies, the researchers concluded that myoepithelial cells figure prominently in the maintenance of the correct 

polarity of the luminal epithelial cells and that direct contact between breast tumor cells and the surrounding fibroblasts causes 

induction of metalloproteinases and other novel genes (Gudjonsson et al., 2004). Another type of three-dimensional human 

cell culture system was used to explore the role of a major signal pathway involving PI3-kinase in polarity and proliferation of 

breast epithelial cells and their malignant counterparts. The study revealed that there are key events in this pathway that have 

distinct roles for maintaining tissue polarity and that disruption of these events is key to the emergence of malignancy (Liu et 

al., 2004).

Genetic and Epigenetic Changes in Breast Cancer Development

Breast cancer resembles most other types of cancer in that multiple genetic or epigenetic events must occur in the 

target cell before it becomes fully malignant. Elucidation of the factors that contribute to mammary tumorigenesis 

is the common goal of many NCI-supported researchers.

The BRCA1 tumor-suppressor gene is involved in the cellular response to DNA damage and plays a key role in maintaining 

genome integrity. Half of all inherited forms of breast cancer contain germline mutations in the BRCA1 gene that ablate its 

function, and an inherited mutation of BRCA1 confers an 85%-90% certainty of female breast cancer by age 70 (Easton et al., 

1995). In addition, a significant proportion of high-grade sporadic breast cancers display reduced levels of BRCA1 mRNA 

and protein, due in part to promoter hypermethylation, a gene-silencing mechanism that is common in human neoplasia 

(Wilson et al., 1999; Esteller et al., 2000). Researchers studying the structure and function of the BRCA1 protein have recently 

identified BRCA1-interacting proteins such as BACH1, BARD1, and RAD51 that implicate the tumor-suppressor protein in a 

variety of cellular activities, including double-strand DNA break repair and transcription of growth inhibitory genes (Cantor et 

al., 2001; Chen et al., 1998; Boulton et al., 2004).

Amplification or overexpression of the Her2/neu receptor tyrosine kinase occurs in about 30% of human breast and ovarian 

cancers and is associated with a more aggressive course of disease for reasons that may be related to increased proliferation, 

vessel formation, and/or invasiveness. A breakthrough for the treatment of Her2/neu-overexpressing tumors occurred in 1998 

with the approval of a new monoclonal antibody-based drug called Herceptin® (trastuzumab). Addition of trastuzumab to the 

standard chemotherapy regimen yielded higher response rates, longer time to disease progression, and a 20% reduction in the 

risk of death in women with metastatic breast cancer (Slamon et al., 2001). A recent study demonstrated that younger women 

with Her2/neu-overexpressing breast cancer had an increased risk of developing a secondary tumor in their contralateral breast 

compared to women whose primary tumors did not overexpress Her2/neu (Li, Malone, et al., 2003). Interestingly, these Her2/

neu-overexpressing cancer cells are more prone to the tumor-promoting effects of ethanol, which was found to increase tumor 

invasiveness through activation of Her2/neu and its downstream signaling components JNK and p38 MAPK (Ma et al., 2003). 

In laboratory studies, ERα-positive breast cancers that overexpress Her2/neu appear to be less responsive to tamoxifen than are 
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Chapter 3: Biology 3-11

breast cancers with low Her2/neu expression. The mechanism behind that observation is in part due to the expression levels 

of an ERα coactivator, AIB1. If patients’ tumors have high levels of both AIB1 and Her2/neu expression, their outcome with 

tamoxifen therapy is very much worse than for either alone (Osborne et al., 2003).

The role of Her2/neu in human cancer and the use of Herceptin® prompted the development of a mouse mammary cancer 

model based on conditional expression of the neu oncogene (Moody et al., 2002). When the oncogene is switched on, the mice 

rapidly develop multiple invasive tumors that readily metastasize to the lungs. When the gene is switched off, which simulates 

treatment with Herceptin®, the tumors regress both at the primary sites and in the lung. However, the lung metastases 

eventually recur, and the tumors are no longer dependent on the initiating event: overexpression of neu. This is also the 

experience with patients who are treated with Herceptin®, who initially respond and have improved survival but whose cancer 

eventually recurs. This model affords the opportunity to study the mechanism of resistance to Herceptin® and to develop more 

effective therapies for these very aggressive human tumors.

Widespread genetic change is a hallmark of human cancers, and breast cancer is no exception. The application of analysis 

tools that permit interrogation of gene expression and genome abnormalities is transforming the rate of discovery of genetic 

alterations. One such tool is chromosomal comparative genomic hybridization (CGH); using this technique, researchers 

evaluated a set of human breast tumors and found two loci at which abnormalities of the number of copies of genes correlated 

with poor survival outcome. They were also able to find a relationship between two other loci and the mutational status of 

p53 (Jain et al., 2001). Such analyses contribute to gene discovery and the development of prognostic markers. Deletions and 

amplifications are frequently observed with CGH; amplicons can be sequenced not only to locate genes, but also to study 

the mechanisms of amplification and their role in cancer progression. One such amplicon at 20q13.2 was comprehensively 

analyzed by a variety of techniques and found to contain two genes that appear to drive the development of breast tumors 

(Collins et al., 2001).

Metastasis and Progression

Complications arising from distant metastases are the eventual cause of death in most breast cancer patients whose tumors have 

spread from their original locations. At diagnosis, approximately 50% of patients with invasive breast cancer have evidence of 

axillary lymph node involvement, and the presence of cancer at this site is a powerful prognostic indicator for early recurrence 

and decreased survival (Fisher et al., 1978; Carter et al., 1989). Depending on the estrogen receptor status of the original 

tumor, further metastases tend to appear in either the bone and reproductive tract (for ER-positive tumors), or viscera (for 

ER-negative tumors) (Koenders et al., 1991). Bone metastases occur frequently in breast cancer patients, are quite painful, 

and are usually fatal. The formation of osteolytic lesions is the result of cooperating events between infiltrating tumor cells and 

resident osteoclasts in the bone. The release of parathyroid hormone-related protein (PTHrP) from tumor cells stimulates the 

resorption of bone through direct or indirect activation of osteoclasts. Increased osteolysis leads to the release of the growth 

factor TGF-β near the tumor site, which in turn stimulates further production of PTHrP by the tumor cells. A vicious cycle is 

thereby propagated in the skeleton, leading to further bone degradation, hypercalcemia, and, eventually, death. NCI-supported 

research has demonstrated that the downstream effects of TGF-β are mediated by the intracellular signaling molecules p38 

MAPK and Smads (Kakonen et al., 2002), and treatment of breast cancer cell lines with a p38 inhibitor was found to prevent 

TGF-β-induced PTHrP production. Researchers have also demonstrated that lifetime exposure to a soluble TGF-β antagonist 

protects mice from metastases in a mouse model of metastatic breast cancer (Yang et al., 2002). These findings have important 

implications for the treatment and prevention of human breast cancer metastases.

Model systems are beginning to reveal some features of the metastatic cascade and the involvement of signal pathways in 

promoting metastasis. One recent study investigated the role of TGF-β signaling in the progression of metastatic events from 

invasion of the primary tumor to the establishment of metastatic foci. The investigators did this by engineering a mouse cancer 

model that can initiate mammary tumors with neu and also express either an activated TGF-β type I receptor or a dominantnegative TGF-β type II receptor (Siegel et al., 2003). The activated type I receptor increased tumor latency and enhanced the 

formation of the lung metastases, while expression of the type II receptor had the opposite effect. Taken together, the results 

point to a role for TGF-β in the successful extravasation of the breast cancer cells from pulmonary vessels. Another mammary 

cancer model was used to study the effect of dietary antioxidants on mammary tumor growth and metastasis. These researchers 
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3-12 Chapter 3: Biology

found that mice fed an antioxidant-depleted diet had more small primary tumors, fewer large primary tumors, and fewer lung 

metastases compared with mice fed a diet with normal levels of vitamins A and E. This study may aid in understanding why 

human intervention trials using antioxidant supplements have produced mixed, and sometimes surprising, results (Albright et 

al., 2004).

Continuing Needs and Evolution

In their 1998 report, PRG members indicated that more research was needed in the area of normal mammary development, 

particularly with regard to understanding the principal cell types involved in mammary development and their mechanisms 

of action. Although the number of projects in NCI’s Breast Cancer Research Portfolio addressing mammary gland biology 

has doubled since the release of the 1998 report, there remains a need for more research in this area. This deficiency 

could be corrected by increasing the funding for new investigators in this field, facilitating the interface between academic 

investigators and biotech/pharmaceutical companies, facilitating the collection of human breast tissue samples from a variety 

of developmental stages, and supporting the development and maintenance of new transgenic or knockout mouse models that 

mimic normal human mammary development.

Progress in breast cancer research would also be accelerated by the integration of biological information across various 

model systems. Data gleaned from experiments in cell lines, ex vivo models, and in vivo models could be incorporated into 

an integrated cancer biology network that uses dynamic computer-based mathematical models, supported by advanced 

informatics systems, to model the development of cancer. These models could recapitulate the interactive, dynamic, and spatial 

relationships between molecules in a cell, between cells, between cells and their microenvironment, and between the organism 

and the macroenvironment during cancer initiation and progression.

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Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH. An adjunct mammary epithelial cell 

population in parous females: its role in functional adaptation and tissue renewal. Development. 2002 Mar;129(6):1377-1386.

Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and 

transdifferentiation. Annu Rev Cell Dev Biol. 2001;17:387-403.

Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA. Sca1 (pos) cells in the mouse mammary gland 

represent an enriched progenitor cell population. Dev Biol. 2002;245:42-56.

Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, 

Kanter MH, Cohen S, Calzone FJ, Slamon DJ. Localization of human BRCA1 and its loss in high-grade, non-inherited breast 

carcinomas. Nat Genet. 1999 Feb;21(2):236-240.

Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, 

Merlino G, Wakefield LM. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without 

adverse side effects. J Clin Invest. 2002 Jun;109(12):1607-1615.

Zan Y, Haag JD, Chen KS, Shepel LA, Wigington D, Wang YR, Hu R, Lopez-Guajardo CC, Brose HL, Porter KI, Leonard 

RA, Hitt AA, Schommer SL, Elegbede AF, Gould MN. Production of knockout rats using ENU mutagenesis and a yeast-based 

screening assay. Nat Biotechnol. 2003 Jun;21(6):645-651.
NCI Breast Cancer Progress Report October 2004

Chapter 4: Etiology 4-1

Chapter 4:

Etiology of Breast Cancer: NCI’s Investment 

and Recent Progress

Research into both the most relevant environmental factors underlying breast cancer and the potential 

inherited susceptibility factors offers a new opportunity for understanding breast cancer risk. Charting 

the Course: Priorities for Breast Cancer Research

Recent research has identified genetic mutations, lifestyle factors, environmental and occupational exposures, and personal 

susceptibility factors that appear to be associated with the development of breast cancer. To learn more about the role of genes 

and gene-environment interactions in the etiology of cancer, NCI is sponsoring the Consortium of Cohorts, which recently 

began pooling data and biospecimens from ten large cohorts (including the Nurses’ Health Study and the Women’s Health 

Study). The Breast and Ovarian Cancer Family Registries collect information and laboratory specimens from 9,000 families 

with a history of breast and/or ovarian cancer to support research on genetic and environmental susceptibility for these 

cancers. NCI is also sponsoring the Long Island Breast Cancer Study Project, a multistudy effort to investigate the role of 

environmental factors in breast cancer in two New York counties.

In its 1998 report, the Breast Cancer PRG identified six priority questions and opportunities that deal with important topics 

in breast cancer etiology research. These priorities address the need to: identify intermediate markers to help advance our 

understanding of breast carcinogenesis, ascertain gene-environment interactions, determine which factors influence disease 

progression, find approaches to expand our knowledge of breast cancer etiology, consider etiologically distinct components of 

breast cancer, and determine the role of dietary factors in breast carcinogenesis.

The NCI has been responsive to the PRG priorities related to breast cancer etiology. Research has recently assessed the breast 

cancer risk of women with mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 who are not 

from multiple-case families. Other genetic mutations have been identified that may also increase a woman’s susceptibility 

to breast cancer. In addition, researchers have determined that several environmental toxins and lifestyle factors (including 

hormone replacement therapy use, exercise, and working at night) appear to be associated with breast cancer risk.

NCI’s Investment and 

Response

From fiscal year 1998 to 2003, NCI’s extramural 

investment in breast cancer etiology research increased 

from $75.3 million to $107.2 million (Figure 4-1). This 

increase corresponds to increases in the number of projects 

that are responsive to the six Breast Cancer PRG research 

priorities for etiology.

NCI’s response to the six Breast Cancer PRG priority 

research questions for etiology is summarized in Table 4-1.1

Figure 4-1. NCI’s extramural investment in 

breast cancer etiology research: 1998-2003 

(in millions of dollars)

1 A given project may map to more than one PRG priority and therefore be represented in more than one figure. Projects active in 2003 are listed in Appendix B (Tables B-7 

to B-13) by Principal Investigator’s name for each PRG priority.

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars
October 2004 NCI Breast Cancer Progress Report

4-2 Chapter 4: Etiology

Table 4-1. NCI Efforts Responsive to PRG Priorities and Opportunities in Etiologya

PRG Priority:

What types of intermediate markers would 

be useful to advance our understanding of 

mechanisms involved in breast carcinogenesis?

NCI Efforts:

■ In FY003, examples of active areas of 

investigation included genes as potential 

markers of accelerated cellular senescence, 

secreted proteins as breast cancer 

prevention markers, the signaling pathways by which heregulin regulates the expression and activation of the urokinase 

plasminogen activator (uPA)/uPA receptor system, and the relationships between breast cancer incidence and plasma 

levels of premenopausal hormones.

■ NCI initiatives addressing this priority included the Cancer Genome Anatomy Project (CGAP), Cancer Molecular 

Analysis Project (CMAP), Cancer Research Small Grant Program, Cooperative Human Tissue Network (CHTN), and 

Director’s Challenge: Toward a Molecular Classification of Cancer.

PRG Priority:

What are the best approaches to understanding geneenvironment interactions?b

NCI Efforts:

■ In fiscal year 2003, examples of active areas of 

investigation included inter-individual variations 

in cancer risk defined by allele variant genes and 

environmental and endogenous risk factors; models of 

cancer that take into account genetic predisposition 

(BRCA 1/2 status), reproductive history, and 

exposure to hormones; the interaction between tobacco smoke and NAT2 or COMT genetic polymorphisms; genetic 

polymorphisms in the genes related to tamoxifen and estrogen bioavailability; and the effect of the timing of dietary 

factors on mammary tumorigenesis and the mechanisms mediating these associations.

■ Examples of clinical trials addressing these priorities included the following:

◆ Comparative Genetic Study of Susceptibility Genotypes and Protein Expression in Healthy Women, Women at 

High Risk for Breast Cancer, and Women With Breast Cancer (NCI-00-C-0079)

◆ Study of Clinical, Genetic, Behavioral, Laboratory, and Epidemiologic Characteristics of Individuals and Families at 

High Risk of Breast or Ovarian Cancer (NCI-02-C-0212)

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

25

50

75

100

125

150

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

a. Some of the original PRG priorities are addressed jointly in Table 4-1 because these priorities address partially overlapping issues and they are relevant to many 

of the same research projects and initiatives.

b. This priority merges the two original PRG priorities: “What are the best approaches to understanding gene-environment interactions?” from the Etiology 

section and “Do any life experiences, behaviors, or environmental exposures influence breast cancer risk among women with inherited mutations in major 

predisposing genes?” from the Genetics section in the original Breast Cancer PRG report.
NCI Breast Cancer Progress Report October 2004

Chapter 4: Etiology 4-3

■ NCI initiatives addressing this priority included Breast and Ovarian Cancer Family Registries (CFRs) and Cancer 

Genetics Network (CGN).

PRG Priority:

What factors influence disease progression?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the association between 

recurrence of breast carcinoma in situ and 

modifiable lifestyle factors, post-treatment 

behavioral risk factors for recurrence of secondary 

breast tumors or new primaries, regulation of 

breast cancer growth by activation peptide, and the role of EGF-related peptides in the pathogenesis of breast and 

colon cancer.

■ NCI initiatives addressing this priority included the Breast Cancer Faculty, the Cancer Genome Anatomy Project, and 

Small Grants Program for Cancer Epidemiology.

PRG Priority:

What might be a useful approach to expanding our 

knowledge regarding breast cancer etiology?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included reasons for ethnic 

variations in cancer incidence; population-based 

case-control studies to investigate the relationship 

between postmenopausal hormone therapy 

and breast cancer mortality and between lifestyle factors and breast cancer incidence; a training program in cancer 

epidemiology, biostatistics, and environmental health sciences; the use of telomerase in new model systems of human 

cancer; and understanding puberty and environmental factors that may influence puberty, the timing of which is an 

important risk factor for breast cancer.

■ On November 1-5, 2003, NCI co-sponsored the 24th Congress of the International Association for Breast Cancer 

Research—Advances in Human Breast Cancer Research: Preclinical Models, as well as a workshop on Genomic and 

Proteomic Technological Advances in Cancer Research.

■ NCI initiatives addressing this priority included 

the Breast and Ovarian Cancer Family Registries, 

Cancer Genetics Network, Cancer Molecular 

Analysis Project, Cooperative Human Tissue 

Network, and NCI Cohort Consortium.

PRG Priority:

Are there etiologically distinct components of breast 

cancer that it would be useful to consider?

0

25

50

75

100

125

150

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

40

80

120

160

200

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year
October 2004 NCI Breast Cancer Progress Report

4-4 Chapter 4: Etiology

NCI Efforts:

■ In FY2003, examples of active areas of investigation included the function of Her4 as a potential differentiation factor 

in human breast cancer, pregnancy hormone levels affecting breast differentiation and proliferation in women with 

different levels of breast cancer risk, and the metabolic factors of obesity/weight changes and indicators of insulin 

status as they relate to breast and endometrial cancers.

■ On November 1-5, 2003, NCI cosponsored the 24th Congress of the International Association for Breast Cancer 

Research—Advances in Human Breast Cancer Research: Preclinical Models, as well as a workshop on Genomic and 

Proteomic Technological Advances in Cancer Research.

■ NCI initiatives addressing this priority included the Breast SPOREs, Cancer Molecular Analysis Project, Director’s 

Challenge: Toward a Molecular Classification of Tumors, and NCI Cohort Consortium.

PRG Priority:

What types of studies should be pursued to 

advance our understanding of the role of dietary 

factors in breast carcinogenesis?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the relationship 

between energy balance and cancer risk in 

African-American women, the association 

between dietary intake of isothiocyanates 

and d-limonene and risk of breast cancer recurrence, the effects of dietary fat and peroxisome proliferator-activated 

receptor gamma on breast cancer progression, and the ability of high-selenium garlic to suppress the clonal expansion 

of mammary preneoplastic lesions.

■ Examples of clinical trials addressing this priority included the following:

◆ Dietary Intervention in Women at High Risk for Breast Cancer (WSU-H-018296)

◆ Randomized Dietary Intervention Study of a Diet Rich in Vegetables, Fruit, and Fiber and Low in Fat in Women 

With Previously Treated Stage I, II, or III Breast Cancer (UCSD-980919)

◆ Phase II Trial of Dietary Fatty Acids: Roles in Hormonally Mediated Cancers in Normal Premenopausal Women 

(UMN-9509M10234)

■ On October 14-16, 1998, NCI sponsored the 5 A Day International Symposium, whose goals included reviewing the 

scientific link between increased consumption of fruits and vegetables and the reduced risk of disease.

■ NCI initiatives addressing this priority included the Cancer Research Small Grant Program and NCI Cohort 

Consortium.

Additional Breast Cancer Etiology Projects

NCI Efforts:

■ Although cancer health disparities were not addressed by this PRG in its report, several areas of investigation on this 

topic were active in FY2003, including the role of diet on breast cancer in Puerto Rican women; the association of 

breast cancer in black and white women with body size, diabetes, and dietary patterns; nutritional and metabolic 

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 4: Etiology 4-5

determinants of cancer in Asian women; and 

differences between gene and antigen expression 

profiles and mutational events in black and white 

women.

■ In FY2003, other examples of active areas of 

investigation included the role of BRCA1 in 

maintaining genome integrity; the complex stromal/

epithelial interactions involved in the initiation and 

development of breast cancer; and the functional 

analysis of breast cancer susceptibility genes in mice.

The initiatives relevant to research on breast cancer etiology between FY1998 and 2003 include the following list of general 

initiatives that are described in Table 2-12 (Chapter 2) and the category-specific initiatives that are listed and described in Table 

4-2.3

■ Aging Women and Breast Cancer

■ Breast and Ovarian Cancer Family Registries (CFRs)

■ Breast Cancer Faculty

■ Cancer Biomedical Informatics Grid (caBIG)

■ Cancer Centers Program

■ Cancer Genetics Services Directory

■ Cancer Genome Anatomy Project (CGAP) 

■ Cancer Research Small Grant Program

■ Cancer Research Training, Career Development, and Education Opportunities 

■ Clinical Trials Cooperative Group Program 

■ Competing Supplements for Organotypic Models of Cancer

■ Cooperative Breast Cancer Tissue Resource (CBCTR)

■ Cooperative Human Tissue Network (CHTN) 

■ Correlative Studies Using Specimens from Multi-Institutional Treatment Trials

■ Director’s Challenge: Toward a Molecular Classification of Tumors

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

■ Improving DNA, RNA, and Protein Availability in Fixed Tissue 

■ Insight Awards to Stamp Out Breast Cancer

■ Minority Institution/Cancer Center Partnership (MI/CCP) 

■ Molecular Target Drug Discovery for Cancer

2 Initiatives that impact multiple categories of breast cancer research.

3 Initiatives that are unique to this chapter on etiology.

0

5

10

15

20

25

30

35

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
October 2004 NCI Breast Cancer Progress Report

4-6 Chapter 4: Etiology

■ Mouse Models of Human Cancers Consortium

■ NCI Center for Bioinformatics (NCICB) 

■ Shared Pathology Informatics Network (SPIN)

■ Shared Resources for Scientists Outside NCI Cancer Centers 

■ Small Animal Imaging Resource Program (SAIRP) 

■ Small Grants Program for Cancer Epidemiology

■ Southern Community Cohort Study (SCCS) 

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer 

■ Specimen Resource Locator

Table 4-2. NCI Initiatives Relevant to Breast Cancer Research: Etiology

Initiatives Focused on Breast Cancer Research

■ Long Island Breast Cancer Study Project (http://epi.grants.cancer.gov/LIBCSP/Overview.html)

◆ Overview: A multistudy effort to investigate whether environmental factors are responsible for breast cancer in 

Suffolk, Nassau, and Schoharie Counties, New York, and in Tolland County, Connecticut.

◆ Relevant Resource Resulting From This Initiative: Findings from the Breast Cancer and the Environment on Long 

Island Study, reported in 2002, found no association between breast cancer and either organochlorine compounds 

such as the pesticide DDT or electromagnetic fields. The study also revealed a small increased risk of developing 

breast cancer in women exposed to polycyclic aromatic hydrocarbons. In this study population, an analysis of 

aspirin and breast cancer risk found that use of this medication was linked to hormone-receptor-positive breast 

cancer but not to hormone-negative breast cancer (Terry et al., 2004). In addition, the NCI developed a healthrelated Geographical Information System (LI-GIS), which provides researchers with an advanced tool to investigate 

relationships between breast cancer and the environment and to estimate exposures to environmental contamination 

in Long Island.

■ Breast Cancer and the Environment Research Centers (RFA-ES-03-001)

◆ Overview: This National Institute of Environmental Health Sciences (NIEHS) and NCI jointly supported initiative 

supports four research centers that will work collaboratively on several fronts. Using animals, they will study the 

development of mammary tissue and the effects of specific environmental agents. In the second collaborative 

project, they will enroll different ethnic groups of young girls and study their life exposures to a wide variety of 

environmental, nutritional, and social factors that impact puberty. Early puberty has been shown to increase breast 

cancer risk later in life. All the centers will work with advocacy groups to add their insight and experience to the 

research effort.

◆ Relevant Projects Resulting From This Initiative:

Puberty and Cancer Initiation: Environment Diet and Obesity

Bay Area Breast Cancer and the Environment Research Center

Breast Cancer and the Environment Research Center

Center for Environment and Mammary Gland Development
NCI Breast Cancer Progress Report October 2004

Chapter 4: Etiology 4-7

■ Regional Variation in Breast Cancer Rates in the U.S. (RFA-CA-98-017)

◆ Overview: Supports interdisciplinary epidemiologic studies to better understand determinants of regional variations 

in breast cancer incidence and mortality rates in the United States.

◆ Relevant Research Projects Resulting From This Initiative: Between 1998 and 2003, five projects relevant to breast 

cancer research were supported through this Request for Applications (RFA). 

Initiatives With Breast Cancer-Relevant Components

■ Cancer Genetics Network (CGN) (http://epi.grants.cancer.gov/CGN)

◆ Overview: A national network of centers specializing in the study of inherited predisposition to cancer.

◆ Relevant Research Projects Resulting From This Initiative: The CGN database contains information from 15,760 

families that have a history of cancer. Data on each enrollee include demographic information, medical history, and 

four-generation family cancer history. Three recent pilot studies addressed issues relevant to breast cancer:

High-Risk Breast Cancer Screening Pilot Study

Validation of BRCA1 and 2 Carrier Probability Models

Genetic and Environmental Modifiers of Penetrance in BRCA1 and BRCA2 Mutation Carriers 

■ Cohort Studies in Cancer Epidemiology (PAS-02-009)

◆ Overview: Coordinates the submission, review, and funding of epidemiologic cohort studies. Cohort studies are well 

suited for the evaluation of gene-gene and gene-environment interactions in a prospective manner.

◆ Relevant Research Projects Resulting From This Program Announcement (PA): Between 1998 and 2003, four 

projects relevant to breast cancer research were supported through this PA. Specific projects can be found in 

Appendix B, Tables B8, B10, and B12, by searching for the PA number.

■ Diet, Lifestyle, and Cancer in U.S. Special Populations (PA-98-028)

◆ Overview: Supports studies to elucidate causes of cancer and means of prevention in African Americans, American 

Indians, Alaska Natives, Asian and Pacific Islanders, Native Hawaiians, Hispanics, and rural, older, low-income, and 

low-literacy groups. These groups experience unusually high cancer incidence and mortality for some cancer sites 

though the environmental and genetic reasons are not well understood.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, three projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B8, B10, and B11, 

by searching for the PA number.

■ Geographic-Based Research in Cancer Control and Epidemiology (PAS-00-120)

◆ Overview: Supports the use of the Atlas of Cancer Mortality in the United States, 1950-1994 to identify the reasons 

for the geographic variation in specific cancers, including the clustering of areas with high or low incidence and/or 

mortality rates.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, one project relevant to breast cancer 

research was supported through this PA:

A Geographic Information System-Based Workbench to Interpret Cancer Maps
October 2004 NCI Breast Cancer Progress Report

4-8 Chapter 4: Etiology

■ Interdisciplinary Studies in the Genetic Epidemiology of Cancer (RFA-CA-98-018)

◆ Overview: Supports collaborative and interdisciplinary genetic epidemiology investigations designed to identify and 

evaluate the interactions of genetic and epidemiologic risk factors leading to cancer susceptibility in individuals, 

families, and populations and factors influencing the rate of increase with age in cancer susceptibility.

◆ Relevant Research Projects Resulting From This RFA: Between 1998 and 2003, one project relevant to breast cancer 

research was supported through this RFA: 

Breast Cancer, Radiation Exposure, and the ATM Gene

■ NCI Cohort Consortium (http://cancercontrol.cancer.gov/bb/cohort_conso.html)

◆ Overview: Large consortium of investigators pooling information on study participants from multiple studies in an 

effort to understand the interaction between cancer-predisposing genes and environmental factors such as chemicals, 

diet, and pharmacological agents.

◆ Relevant Resources Resulting From This Initiative: High-quality exposure and cancer data from 700,000 individuals 

and their biological specimens will be used for genetic analysis studies. A first “proof of principle” study will focus on 

breast and prostate cancer and seek to identify important gene-environment interactions in hormonal synthesis and 

metabolic pathways.

Ongoing NCI Research: Recent Progress in Breast Cancer 

Etiology

BRCA1 and BRCA2

Mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 are observed in a large proportion of 

families in which several members have had breast cancer. As commercial testing for BRCA1 mutations has become accepted, 

more BRCA1 mutation carriers are being identified in cancer risk evaluation programs. Some women in these programs who 

learn that they have these mutations choose to undergo prophylactic mastectomy and/or oophorectomy because of their 

extremely high cancer risk—78% according to one cancer risk evaluation program, in comparison to a lifetime risk estimate of 

13% for all women (Brose et al., 2002; Ries et al., 2004). Research has recently addressed the breast cancer risk of women with 

mutations in BRCA1 or BRCA2 who are not from multiple-case families.

One study found that Ashkenazi Jewish women who inherited mutations in the BRCA1 and BRCA2 genes had an 82% 

lifetime risk of breast cancer—similar to that of women in families with many breast cancer cases (King et al., 2003). Another 

study showed that women who carry BRCA1 mutations have a higher average risk of breast cancer (65%) than BRCA2 carriers 

(45%), but this difference decreases after age 50 (Antoniou et al., 2003). For women with BRCA1 mutations, those identified 

who are referred to or seek counseling at cancer risk evaluation clinics have a higher risk of breast cancer (73%) than women in 

population-based studies (35%-50%) and a lower risk than women from multiple-case families (Brose et al., 2002).

Research is also addressing behavioral modifiers of breast cancer risk among BRCA1 and BRCA2 carriers. One study found 

that taking oral contraceptives was not associated with an increased risk of breast cancer among BRCA2 mutation carriers. But 

BRCA1 mutation carriers who had ever used oral contraceptives—especially if they had used them for more than 5 years or 

before age 30—had an increased risk of developing early-onset breast cancer (Narod et al., 2002). Although previous research 

indicated that smoking increased the risk of developing hereditary breast cancer, a recent study found no significant impact on 

breast cancer risk in BRCA1 or BRCA2 carriers who were current or previous smokers (Ghadirian et al., 2004).
NCI Breast Cancer Progress Report October 2004

Chapter 4: Etiology 4-9

Other Breast Cancer Susceptibility Genes

BRCA1 and BRCA2 gene mutations can increase breast cancer risk substantially, but these mutations are rare and explain 

only a small proportion of the clustering of breast cancer in certain families. According to recent research, only 5%-10% of 

breast cancers diagnosed in women younger than 40 years can be attributed to mutations in these genes (Dite et al., 2003). 

Researchers are therefore studying other candidate susceptibility genes.

One possibility is CHEK2, a gene that encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes 

involving BRCA1 and p53. Researchers have found that a variant of CHEK2, CHEK2(*)1100delC, is found in 1.1% of 

healthy individuals, 5.1% of individuals with breast cancer from families that do not carry mutations in BRCA1 or BRCA2, 

and 13% of individuals from families with male breast cancer. The investigators estimate that this variant increases breast 

cancer risk about twofold in women and tenfold in men, although it does not increase risk in carriers of BRCA1 or BRCA2 

mutations (Meijers-Heijboer et al., 2002).

Another potential susceptibility gene is the ATM gene, which is mutated in ataxia-telangiectasia. One analysis found two ATM 

mutations (IVS10–6T®G and T7271G) in 4% of families with multiple breast cancer cases that did not carry the BRCA1 or 

BRCA2 mutations. The risk associated with these mutations was strong enough for them to cause multiple cases in families 

(Chenevix-Trench et al., 2002). Another study found several variants of ATM in families with a history of breast cancer, 

ovarian cancer, or both, but not in families with no history of breast cancer (Thorstenson et al., 2003).

Other genes that may play a role in influencing breast cancer risk independently or together with other environmental, 

behavioral, or endogenous factors include those involved in estrogen synthesis, such as CYP19 (Han et al., 2004), and DNA 

repair, such as members of the XRCC gene family (Haiman et al., 2003).

Environmental Influences

Several environmental pollutants have been hypothesized to be involved in the development of breast cancer. The Long 

Island Breast Cancer Study Project is a federally mandated, population-based case-control study sponsored in part by NCI 

to determine whether breast cancer risk among women in Nassau and Suffolk Counties, New York, is associated with certain 

environmental exposures.

The Long Island investigators found little evidence of an increased risk of breast cancer from exposure to organochlorines, 

including the pesticide DDT and the industrial chemical PCBs, based on assessments of the levels of these chemicals in blood 

(Gammon et al., 2002b). In addition, analysis of extensive electromagnetic field exposure measurements in this population 

yielded evidence that electromagnetic field exposure was not a risk factor for breast cancer (Schoenfeld et al., 2003). The Long 

Island Study researchers also investigated the association between polycyclic aromatic hydrocarbon (PAH) compounds—some 

of which have been categorized by the Environmental Protection Agency as probable or possible human carcinogens—and 

breast cancer risk. Major sources of human exposure to PAH compounds include combustion products of fossil fuels and 

cigarette smoking, as well as grilled and smoked foods. The investigators found that women with high PAH-DNA adduct levels 

had a 50% higher risk of breast cancer than women with lower adduct levels, although they observed no dose-response effect 

(Gammon et al., 2002a).

Behavioral Factors

Millions of women in the United States have taken hormone replacement therapy (HRT) to relieve menopausal symptoms and 

prevent chronic diseases, including heart disease and osteoporosis. But recent research has shown that the benefits of HRT are 

limited to management of menopausal symptoms and the prevention of osteoporosis and colorectal cancer. However, results of 

the Women’s Health Initiative trial of combined estrogen and progestin showed that overall health risks exceed these benefits. 

The study showed that relatively short-term use of combined estrogen and progestin increases the risk of cardiovascular disease, 

blood clots, and breast cancer and that these cancers are more likely to be diagnosed at more advanced stages in women using 

the therapy than in women not using the therapy (Chlebowski et al., 2003). Another study showed that women who take 

combined estrogen and progestin regimens increase their risk of breast cancer each year by about twice as much as women who 

take estrogen alone (Newcomb et al., 2002).
October 2004 NCI Breast Cancer Progress Report

4-10 Chapter 4: Etiology

Obesity is a known risk factor for breast cancer. Recent research has shown that heavier postmenopausal women (body mass 

index [BMI] >31), especially postmenopausal women under the age of 65, have more than twice the breast cancer risk of 

slimmer women (BMI <23). Changes in BMI and weight since age 18 were also found to be associated with breast cancer. 

Some studies suggest that obesity is a risk factor only among women who have never taken HRT (Morimoto et al., 2002). 

Other investigators have shown that women can reduce their breast cancer risk through exercise. Sustained activity throughout 

life, and especially activity after menopause, can reduce the risk of breast cancer substantially (Friedenreich et al., 2001).

Endogenous Factors

Some potentially important new predictors of risk have been identified through the prospective Nurses’ Health Study. 

Researchers have identified a positive relationship between levels of circulating insulin-like growth factor and breast cancer risk 

in premenopausal women (Hankinson et al., 1998). An association has also been found between plasma prolactin, a hormone 

that is essential for mammary gland development and lactation, and breast cancer risk. Women with high levels of prolactin 

have about twice the breast cancer risk of women with low levels of the hormone (Hankinson et al., 1999). Levels of another 

hormone, melatonin, may have an impact on breast cancer risk. Melatonin serum levels decrease when people are exposed to 

light at night. When researchers tested nurses who work night shifts, they found that women who worked on rotating night 

shifts had a greater risk of breast cancer than those who never worked these shifts; these risks were highest in women who had 

worked night shifts for 30 or more years (Schernhammer et al., 2001).

Continuing Needs and Evolution

A promising direction of genetics research is to develop prevention, screening, and prognostic applications; however, progress 

in understanding how genes and specific genotype patterns affect risk for breast cancer has been limited by the design and 

size of genetic studies. For some of the genes that appear to be associated with the risk of breast cancer development or 

progression, the small scale of the studies has led to contradictory results among different research groups. Large-scale, multiinstitutional studies are now being conducted to validate the association and causation of putative susceptibility genes with 

breast cancer risk, incorporating advanced genomic analyses by haplotyping and genomic scans to address the complexities of 

genetic and environmental interrelationships. Genetic etiology studies are collecting and analyzing data on other lifestyle and 

environmental factors to identify linkages between certain genes and the environment. The development of nationwide and 

international cohorts requires a standardized mechanism for collecting, analyzing, and reporting data and enhanced resources 

to support these studies.

There is a continuing need to improve the estimates of the magnitude of risk associated with BRCA1 and certain other 

mutations. While these genes are clearly important, there are a number of different mutations involved, and the risk estimates 

for developing breast cancer vary widely—in part because of differences in study designs. Women who consider being tested 

for mutations in these genes need to make decisions based on the best possible estimates of risk, as being tested has profound 

implications for both the women who are tested and their family members in terms of quality of life and medical decisions 

regarding the potential use of preventive measures (e.g., chemoprevention or surgical procedures).

A better understanding is needed of the role of endogenous hormones—especially hormones that have not been well studied 

with respect to breast cancer, such as prolactin and progesterone. It is also important to understand exogenous and lifestyle 

factors that contribute to endogenous hormone levels. Techniques are needed to better measure hormones, understand their 

interrelationships, and clarify how peripheral measurement of hormones is related to local production in breast tissue. Such 

information may be useful in further developing chemopreventive approaches given evidence showing that tamoxifen has 

protective effects against the development of breast cancer.
NCI Breast Cancer Progress Report October 2004

Chapter 4: Etiology 4-11

NCI-Supported Research Referenced in Chapter 4

Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, 

Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius 

H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, 

Easton DF. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series 

unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003 May;72(5):1117-1130.

Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation 

carriers identified in a risk evaluation program. JNCI. 2002 Sep 18;94(18):1365-1372.

Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, 

Scott C, Pupo GM, Dork T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK. 

Dominant negative ATM mutations in breast cancer families. JNCI. 2002 Feb 6;94(3):205-215.

Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson 

CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators. Influence of estrogen plus progestin on breast cancer 

and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003 Jun 

25;289(24):3243-3253.

Dite GS, Jenkins MA, Southey MC, Hocking JS, Giles GG, McCredie MR, Venter DJ, Hopper JL. McCredie MRE, enter 

DJ, Hopper JL. Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. JNCI. 2003 Mar 

19;95(6);448-457.

Friedenreich CM, Courneya KS, Bryant HE. Influence of physical activity in different age and life periods on the risk of breast 

cancer. Epidemiology. 2001 Nov;12(6):604-612.

Gammon MD, Santella RM, Neugut AI, Eng SM, Teitelbaum SL, Paykin A, Levin B, Terry MB, Young TL, Wang LW, Wang 

Q, Britton JA, Wolff MS, Stellman SD, Hatch M, Kabat GC, Senie R, Garbowski G, Maffeo C, Montalvan P, Berkowitz G, 

Kemeny M, Citron M, Schnabel F, Schuss A, Hajdu S, Vinceguerra V. Environmental toxins and breast cancer on Long Island. 

I. Polycyclic aromatic hydrocarbon DNA adducts. Cancer Epidemiol Biomarkers Prev. 2002a Aug;11(8):677-685.

Gammon MD, Wolff MS, Neugut AI, Eng SM, Teitelbaum SL, Britton JA, Terry MB, Levin B, Stellman SD, Kabat GC, 

Hatch M, Senie R, Berkowitz G, Bradlow HL, Garbowski G, Maffeo C, Montalvan P, Kemeny M, Citron M, Schnabel F, 

Schuss A, Hajdu S, Vinceguerra V, Niguidula N, Ireland K, Santella RM. Environmental toxins and breast cancer on Long 

Island. II. Organochlorine compound levels in blood. Cancer Epidemiol Biomarkers Prev. 2002b Aug;11(8):686-697.

Ghadirian P, Lubinski J, Lynch H, Neuhausen SL, Weber B, Isaacs C, Baruch RG, Randall S, Ainsworth P, Freidman E, 

Horsman D, Tonin P, Foulkes WD, Tung N, Sun P, Narod SA. Smoking and the risk of breast cancer among carriers of BRCA 

mutations. Int J Cancer. 2004 Jun 20;110(3):413-416.

Haiman CA, Stram DO, Pike MC, Kolonel LN, Burtt NP, Altshuler D, Hirschhorn J, Henderson BE. A comprehensive 

haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort. Hum Mol Genet. 2003 Oct 15;12(20):2679-

2692. Epub 2003 Aug 27.

Han J, Hankinson SE, Zhang SM, De Vivo I, Hunter DJ. Interaction between genetic variations in DNA repair genes and 

plasma folate on breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):520-524.

Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating 

concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998 May 9;351(9113);1393-1396.

Hankinson SE, Willett WC, Michaud DS, Manson JE, Colditz GA, Longcope C, Rosner B, Speizer FE. Plasma prolactin 

levels and subsequent risk of breast cancer in postmenopausal women. JNCI. 1999 Apr 7;91:629-634.

King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited 

mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-646.
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Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, 

Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, 

Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday 

V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber 

B, Rahman N, Stratton MR. CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to 

CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002 May;31(1):55-59.

Morimoto LM, White E, Chen Z, Chlebowski RT, Hays J, Kuller L, Lopez AM, Manson J, Margolis KL, Muti PC, Stefanick 

ML, McTiernan A. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United 

States). Cancer Causes Control. 2002 Oct;13(8):741-751.

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Isaacs C, Weber B, Friedman E, Gershoni-Baruch R, Rennert G, Pasini B, Wagner T, Daly M, Garber JE, Neuhausen SL, 

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Weitzel J, Merajver S, Gauthier-Villars M, Jernstrom H, Sun P, Brunet JS. Oral contraceptives and the risk of breast cancer in 

BRCA1 and BRCA2 mutation carriers. JNCI. 2002 Dec 4;94(23):1773-1779.

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Postmenopausal estrogen and progestin use in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2002 

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3333.
NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-1

Chapter 5:

Breast Cancer Prevention: NCI’s Investment 

and Recent Progress

The goal of breast cancer prevention research is to develop readily acceptable, minimally toxic, and 

affordable strategies that will reduce breast cancer incidence, morbidity, and mortality without inducing 

increased morbidity and mortality from other conditions. Charting the Course: Priorities for Breast 

Cancer Research

Recent advances in fields of biology, genetics, and epidemiology have led to an increased understanding of the risk factors 

that predispose certain individuals to cancer. It has become clear in recent years that certain genetic, hormonal, dietary, and 

other lifestyle influences play an important role in the development of breast malignancies. These influences may be mediated 

indirectly by several factors, such as early full-term pregnancy or exercise. The NCI continues to address the challenges of 

identifying the relevant risk factors and enabling the development of effective preventive agents and strategies that delay or 

inhibit the clinical onset of invasive disease. Prevention research is also aimed at reducing the incidence of secondary breast 

tumors that may arise in the months or years following treatment for the initial breast cancer.

In 1998, the Breast Cancer PRG identified seven priorities that deal with important topics in breast cancer prevention research. 

These priorities address the need to create models of precancerous biology, identify surrogate endpoint biomarkers of breast 

cancer development, determine the essential changes in breast cancer initiation, determine the efficacy of preclinical prevention 

trials, increase the number of Phase II trials that test novel preventive agents and strategies, increase the efficiency of accrual to 

Phase III clinical trials, and effectively use human models to determine the optimal dosage of chemopreventive agents.

The NCI has been responsive to PRG priorities related to breast cancer prevention. Genetic mutations comparable to their 

human disease counterparts have been used to construct mouse models that develop precancerous lesions as well as breast 

cancer. These models provide a wealth of information about factors involved in breast cancer initiation and have been used to 

determine the effectiveness of a variety of agents and strategies for the prevention of breast cancer. A large-scale NCI-sponsored 

clinical trial led to FDA approval of tamoxifen as a chemopreventive agent in high-risk women, and NCI-sponsored researchers 

are pursuing trials that will assess the effectiveness of other chemotherapeutic regimens in reducing breast cancer incidence.

NCI’s Investment and 

Response

From FY1998 to 2003, NCI’s extramural investment in 

breast cancer prevention research increased from $28.9 

million to $43.7 million (Figure 5-1). This increase in 

funding corresponds to increases in the number of projects 

that are responsive to the seven Breast Cancer PRG research 

priorities for prevention.

NCI’s responsiveness to breast cancer prevention research is 

summarized in Table 5-1 for the seven original PRG prevention 

priorities and two of the original PRG genetics priorities.1

Figure 5-1. NCI’s extramural investment in 

breast cancer prevention research: 1998-2003 

(in millions of dollars)

0

10

20

30

40

50

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars

1 A project may map to more than one PRG priority and therefore be represented in more than one figure. Projects active in 2003 are listed by Principal Investigator’s name 

for each PRG priority in Appendix B (Tables B-14 to B-23).
October 2004 NCI Breast Cancer Progress Report

5-2 Chapter 5: Prevention

Table 5-1. NCI Efforts Responsive to PRG Priorities and Opportunities in Prevention

PRG Priority:

Better models of precancerous biology are urgently 

needed. These include animal and xenograft models, 

human precancerous cell lines, and in vivo human 

precancerous models for long-term study.

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included growth of human tumor cell lines in 

protein-free/hormone-free media, mammary 

tumorigenesis in inbred and feral mice, breast 

cancer development in female mice from a transgenic model of prostate cancer, functional analysis of breast cancer 

susceptibility genes in mice, prevention of mammary cancer in Her2/neu transgenic mice, new models of human 

cancer, screening various chemopreventive agents, MNU-induced rat mammary tumors, and human cell-based 

systems for screening chemopreventive agents in vitro.

■ Examples of evolving preclinical chemopreventive agent screening systems include normal human mammary epithelial 

cells that spontaneously escape senescence and acquire genomic changes (Romanov et al., 2001) and prevention of 

breast epithelial cell immortalization with chemopreventive and antitelomerase agents (Herbert et al., 2001).

■ On September 5-6, 2002, NCI sponsored the Nutritional Genomics and Proteomics in Cancer Prevention meeting, 

which included workshops on model systems.

■ NCI initiatives addressing this priority included Competing Supplements for Organotypic Models of Cancer and the 

Mouse Models of Human Cancer Consortium.

PRG Priority:

Delineate the key surrogate endpoint biomarkers 

(SEBs) for breast cancer development.

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included biological markers of 

breast cancer and tamoxifen response, biomarker 

modulation by COX-2 inhibitors, detection of 

breast cancer protein signatures in body fluid, 

characterization of a novel breast-specific mucin gene, molecular characterization of breast basal-like tumors, p53 in 

benign breast disease and breast cancer risk, preclinical evaluations of candidate intermediate endpoints and their 

modulation by chemopreventive agents, and the molecular profile of inflammatory breast cancer.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase II Chemoprevention Study of Celecoxib in Premenopausal Women at High Risk for Estrogen ReceptorNegative Breast Cancer (KUMC-HSC-8919-02)

◆ Randomized Chemoprevention Study of Bexarotene in Women at High Genetic Risk for Breast Cancer 

(BCM-H-9315)

0

20

40

60

80

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

10

20

30

40

50

60

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-3

■ NCI initiatives addressing this priority included the Cancer Genome Anatomy Project (CGAP), Cancer Prevention 

Research Small Grants Program, and Cooperative Human Tissue Network (CHTN).

PRG Priority:

Determine the degree to which preclinical prevention 

trials are indicative of outcomes in humans.

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the use of human 

prolactin antagonist as a chemopreventive agent, 

combination chemoprevention of estrogen receptor 

(ER)-negative breast cancer, synthetic peptides 

from alpha-fetoprotein that prevent breast cancer, 

multiantigen vaccines for breast cancer prevention, molecular biomarkers of selenium chemoprevention, prevention of 

breast cancer using selective retinoids, and modulation of carcinogenesis by monoterpenoids.

■ NCI initiatives addressing this priority included Chemoprevention in Genetically-Identified High-Risk Groups and 

Chemoprevention of Estrogen Receptor (ER)-Negative Breast Cancer: Preclinical Studies.

PRG Priority:

Increase the number of new agents and strategies 

evaluated by increasing the number of Phase II 

pivotal trials, with biomarker modulation as the 

measure of efficacy.

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included a trial to assess the impact 

of a low-fat diet on breast cancer recurrence, 

a chemoprevention pilot trial examining the 

influence of tamoxifen on candidate surrogate endpoint biomarkers, the effect of phytochemicals on estrogenenhanced cancers, the role of antioxidants in breast cancer prevention, and EGFR pathway modulation in ductal 

carcinoma in situ.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase II Randomized Study of Polyphenon E (Green Tea Extract) and Low-Dose Aspirin in Women at High Risk 

for Developing Breast Cancer (UCLA-0305011)

◆ An Exploratory Study to Identify Potential Surrogate Endpoint Biomarkers That Are Modulated by Tamoxifen vs. 

Placebo in Women with an Increased Risk for Breast Cancer (UTSWMC #0799-302, N01-CN-95139)

◆ Phase II Chemoprevention Study of Celecoxib in Premenopausal Women at High Risk for Estrogen ReceptorNegative Breast Cancer (KUMC-HSC-8919-02)

■ On October 22, 2001, NCI sponsored the workshop Clinical Trial Design for the Molecular Targets Faculty. On July 

28-August 3, 2001, NCI sponsored the American Society of Clinical Oncology (ASCO)–American Association for 

Cancer Research (AACR) Educational Workshop: Methods in Clinical Cancer Research.

0

5

10

15

20

25

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

5-4 Chapter 5: Prevention

■ NCI initiatives addressing this priority included Chemoprevention in Genetically Identified High-Risk Groups, 

Community Clinical Oncology Program (CCOP), and the Rapid Access to Preventive Intervention Development 

(RAPID) Program.

PRG Priority:

Increase Phase III accrual efficiency and maximize 

scientific information gleaned (e.g., validation of SEB 

and conduct of behavioral and outcomes research).

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included an exercise intervention 

study to combat fatigue in cancer patients and 

numerous clinical trials conducted at community 

clinical oncology program sites.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase III Randomized Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer 

(NASBP-P-2)

■ NCI initiatives addressing this priority included the Clinical Trials Cooperative Group Program, Community Clinical 

Oncology Program (CCOP), and Minority-Based CCOPs.

PRG Priority:

What are the essential changes in breast cancer 

initiation?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the biology of vascular 

epithelial growth factors in the mammary gland, 

signal transduction pathways of TGF-β, the role of 

CCAAT/enhancer-binding protein transcription 

factors in regulating cell growth and tumorigenesis, 

p53 in benign breast disease and breast cancer risk, p27KIPL deficiency as a potential promoter of carcinogenesis, the 

role of fibroblasts and IGF-II in breast carcinogenesis, nucleoside transporters as chemoprevention targets, and Xlinked genes in breast and ovarian cancer etiology.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase II Chemoprevention Study of Celecoxib in Premenopausal Women at High Risk for Estrogen ReceptorNegative Breast Cancer (KUMC-HSC-8919-02)

◆ Phase II Randomized Chemoprevention Study of LY353381 Hydrochloride in Women With Fine Needle Aspiration 

Cytologic Evidence of Hyperplasia and at High Risk for Breast Cancer (KUMC-HSC-7264-97)

■ NCI initiatives addressing this priority included the Cancer Molecular Analysis Project (CMAP) and Cooperative 

Breast Cancer Tissue Resource (CBCTR).

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-5

PRG Priority:

Are we using appropriate human models in Phase 

I and II testing for optimal chemoprevention dose 

range finding?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included a trial of aspirin and 

vitamin E in women.

■ Examples of clinical trials addressing this priority 

included the following:

◆ Phase I Study of Perillyl Alcohol in Women at Risk for Recurrent Breast Cancer (CCF-IRB-3574)

◆ Phase II Randomized Chemoprevention Study of LY353381 Hydrochloride in Women With Fine Needle Aspiration 

Cytologic Evidence of Hyperplasia and at High Risk for Breast Cancer (KUMC-HSC-7264-97)

◆ Phase II Randomized Study of Polyphenon E (Green Tea Extract) and Low-Dose Aspirin in Women at High Risk 

for Developing Breast Cancer (UCLA-0305011)

■ An NCI initiative addressing this priority was Chemoprevention in Genetically-Identified High-Risk Groups: 

Interactive Research and Development Projects.

PRG Priority:

What is the efficacy of chemopreventive drugs in 

reducing breast cancer risk among women with 

inherited predisposition?a

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included chemoprevention for 

women at high risk of breast cancer, new 

triterpenoids for chemoprevention of cancer, 

chemoprevention of breast and ovarian cancer, and 

biomarker modulation by COX-2 inhibitors.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase I Study of Perillyl Alcohol in Women at Risk for Recurrent Breast Cancer (CCF-IRB-3574)

◆ Phase II Chemoprevention Study of Celecoxib in Premenopausal Women at High Risk for Estrogen ReceptorNegative Breast Cancer (KUMC-HSC-8919-02)

◆ Phase II Randomized Chemoprevention Study of LY353381 Hydrochloride in Women With Fine Needle Aspiration 

Cytologic Evidence of Hyperplasia and at High Risk for Breast Cancer (KUMC-HSC-7264-97)

◆ Phase II Randomized Study of Polyphenon E (Green Tea Extract) and Low-Dose Aspirin in Women at High Risk 

for Developing Breast Cancer (UCLA-0305011)

0

4

8

12

16

20

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

a This priority was part of the Genetics section in the original Breast Cancer PRG report.

0

2

4

6

8

10

12

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

5-6 Chapter 5: Prevention

◆ Randomized Chemoprevention Study of Bexarotene in Women at High Genetic Risk for Breast Cancer 

(BCM-H-9315)

◆ Phase III Randomized Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer 

(NASBP-P-2)

■ On July 7-8, 1998, NCI sponsored the Breast Cancer Prevention Trial (BCPT) Workshop. On April 26-28, 2000, 

NCI sponsored the NIH Selective Estrogen Receptor Modulators (SERMs) Workshop. On December 11-12, 2000, NCI 

sponsored the U.S. Preventive Services Taskforce meeting.

■ The NCI initiative addressing this priority was Chemoprevention in Genetically-Identified High-Risk Groups: 

Interactive Research and Development Projects.

PRG Priority:

What is the efficacy of prophylactic mastectomy and 

prophylactic oophorectomy?b

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included patient-oriented outcomes 

of prophylactic mastectomy, a prospective study of 

risk-reducing salpingo-oophorectomy and ovarian 

screening among women at increased genetic 

risk of breast and ovarian cancer, and the role of prophylactic surgery in reducing breast and ovarian cancer risk and 

mortality in BRCA1 and BRCA2 mutation carriers.

Additional Breast Cancer Prevention Projects

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included cancer prevention in 

medical education practice, breast cancer risk 

assessment with Bayesian networks, p53 loss in 

human mammary epithelial cells as a model of 

breast cancer prevention, impact of mortality 

concerns on cancer risk behavior, and breast 

cancer prevention in female survivors of Hodgkin’s 

disease.

■ Active research projects in FY2003 related to reducing breast cancer health disparities included epidemiologic studies 

of diet and cancer in Hawaii, which explores etiologic factors for ethnic variations in cancer incidence and the study of 

energy balance and breast cancer in black and white women, which examines the relationship between energy balance 

and insulin resistance-related factors with the age-specific incidence of breast cancer in black and white women in the 

United States.

b This priority was part of the Genetics section in the original Breast Cancer PRG report.

0

1

2

3

4

5

6

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

5

10

15

20

25

30

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-7

Much of NCI’s investment in breast cancer prevention research has focused on the identification of breast cancer risk factors 

and the evaluation of potential chemopreventive regimens for their ability to inhibit or delay the onset of clinical disease. 

The initiatives relevant to research on breast cancer prevention between 1998 and 2003 include the following list of general 

initiatives that are described in Table 2-1,2 as well as the category-specific initiatives that are described in Table 5-2.3

■ Aging Women and Breast Cancer

■ Basic and Preclinical Research on Complementary Alternative Medicine (CAM)

■ Breast and Ovarian Cancer Family Registries

■ Breast Cancer Faculty

■ Breast Cancer Surveillance Consortium (BCSC)

■ Cancer Biomedical Informatics Grid (caBIG)

■ Cancer Centers Program

■ Cancer Genome Anatomy Project (CGAP)

■ Cancer Molecular Analysis Project (CMAP)

■ Cancer Research Small Grants Program

■ Cancer Research Training, Career Development and Education Opportunities 

■ Clinical Trials Cooperative Group Program 

■ Community Clinical Oncology Program (CCOP)

■ Competing Supplements for Organotypic Models of Cancer

■ Cooperative Breast Cancer Tissue Resource (CBCTR)

■ Cooperative Human Tissue Network (CHTN)

■ Correlative Studies Using Specimens from Multi-Institutional Treatment Trials

■ Director’s Challenge: Toward a Molecular Classification of Tumors

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

■ Insight Awards to Stamp Out Breast Cancer

■ Integrating Aging and Cancer Research

■ Interdisciplinary Research Teams for Molecular Target Assessment 

■ In Vivo Cellular and Molecular Imaging Centers (ICMICs) 

■ Minority Institution/Cancer Center Partnership (MI/CCP)

■ Minority-Based Community Clinical Oncology Program (MBCCOP) 

■ Molecular Target Drug Discovery for Cancer 

■ Mouse Models of Human Cancers Consortium

■ NCI Center for Bioinformatics (NCICB)

 2 Initiatives that impact multiple categories of breast cancer research.

 3 Initiatives that are unique to this chapter on prevention.
October 2004 NCI Breast Cancer Progress Report

5-8 Chapter 5: Prevention

■ Shared Pathology Informatics Network (SPIN)

■ Shared Resources for Scientists Outside NCI Cancer Centers 

■ Small Animal Imaging Resource Program (SAIRP)

■ Southern Community Cohort Study

■ Special Populations Networks

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer

■ Specimen Resource Locator 

■ Therapeutic Modulation of Angiogenesis in Disease

Table 5-2. NCI Initiatives Relevant to Breast Cancer Research: Preventiona

Initiatives Focused on Breast Cancer

■ Chemoprevention of Estrogen Receptor (ER)-Negative Breast Cancer Preclinical Studies (RFA-CA-03-005)

◆ Overview: Supports the development and evaluation of preclinical chemopreventive strategies that could be rapidly 

translated to clinical studies and are applicable to women at high risk for development of ER-negative breast cancer.

◆ Relevant Research Projects Resulting From This Initiative: Between 1998 and 2003, six projects relevant to breast 

cancer research were supported through this RFA. Specific projects can be found in Appendix B, Tables B2, B7, 

B10, B11, B14-16, and B19, by searching for the PA number.

■ Study of Tamoxifen and Raloxifene (STAR) Trial (http://www.cancer.gov/star)

◆ Overview: A major clinical trial with the goal of determining whether the osteoporosis drug raloxifene is as effective 

as tamoxifen in preventing breast cancer in postmenopausal women who are at high risk for developing breast 

cancer.

◆ Relevant Resource Resulting From This Initiative: This project finished accrual in June 2004 of more than 19,000 

volunteers who were randomized to use the intervention drug for a period of 5 years. Women from more than 

400 sites across the United States, Puerto Rico, and Canada joined the effort. The Data and Safety Monitoring 

Committee for the trial will assess results on a periodic basis to determine when the conditions are met to publish 

results. The goal of the trial is to determine if raloxifene is comparable to tamoxifen in preventing breast cancer. If 

that is the case, then the preferred Selective Estrogen Receptor Modulator (SERM) for breast cancer prevention will 

be established on the basis of which agent has a more favorable risk-benefit profile. A full listing of STAR sites and 

important trial information, including updates, are available at the National Surgical Adjuvant Breast and Bowel 

Project (NASBP) Web site: www.nsabp.pitt.edu/.

Initiatives With Breast Cancer-Relevant Components

■ Chemoprevention in Genetically-Identified High-Risk Groups: Interactive Research and Development Projects 

(RFA-CA-98-012)

◆ Overview: Supports the establishment of integrated, multidisciplinary research programs that define and evaluate 

chemopreventive strategies in asymptomatic subsets of individuals at high risk for cancer.

a Lists of the projects derived from each initiative can be located on the online Supplement to the Breast Cancer Progress Report: Initiative Database.
NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-9

◆ Relevant Projects Resulting From This RFA: Between 1998 and 2003, one project relevant to breast cancer research 

was supported through this RFA:

Chemoprevention of Breast and Ovarian Cancer

■ Phase I and II Cancer Prevention Clinical Trials Consortia 

(http://www.cancer.gov/newscenter/pressreleases/preventtrials)

◆ Overview: Consortium of research centers designed to conduct early-phase cancer prevention clinical trials.

◆ Relevant Resource Resulting From This Initiative: In 2003, six institutions were initially supported to conduct 

cancer prevention clinical trials to assess the potential of new agents. As part of the clinical trials, consortia members 

are expected to conduct studies on biological markers associated with cancer development and studies that elucidate 

mechanisms of cancer prevention. New consortium institutions include:

University of Arizona

University of California, Irvine

Northwestern University

Mayo Clinic Foundation

University of Texas M. D. Anderson Cancer Center

University of Wisconsin, Madison

■ Rapid Access to Preventive Intervention Development (RAPID) Program (http://www3.cancer.gov/prevention/rapid/

index.html)

◆ Overview: Expedites the movement of novel molecules and concepts from the laboratory to the clinic for clinical 

trials of efficacy.

◆ Relevant Research Projects Resulting From This Initiative: Since its inception in 2000, the RAPID program has 

provided assistance for 24 specific projects, which are listed on the RAPID Projects Web site. Three of these projects 

have direct relevance to breast cancer:

Development of alpha-TEA, a Novel Tocopherol-Based Anticancer Agent, for Prevention of Breast Cancer 

Recurrence and Metastasis

Preclinical Development of 9-cis-UAB30 for Breast Cancer Chemoprevention

Preclinical Development of Four Flavonoids from Broussonetia papyrifera

Ongoing NCI Research: Recent Progress in Breast Cancer 

Prevention

Models of Precancerous Biology

NCI-supported research groups have developed valuable strains of mice that replicate various features of breast carcinogenesis 

in humans. These mouse models of breast carcinogenesis can be used to test the efficacy of chemopreventive agents. The neu 

transgenic mouse, which contains an activated form of the c-neu oncogene, develops estrogen receptor (ER)-negative breast 

tumors that resemble those found in approximately 25% of all women with breast carcinoma (Muller et al., 1988). These mice 

provide a useful animal model for the evaluation of intervention strategies to delay/prevent breast cancer and have been used to 

demonstrate the effectiveness of celecoxib (a COX-2 inhibitor) and gefitinib (an EGFR inhibitor) in the prevention of breast 

cancer (Howe et al., 2002, Lu et al., 2003). Likewise, conditional knockout of the BRCA-1 gene in the mammary epithelium 
October 2004 NCI Breast Cancer Progress Report

5-10 Chapter 5: Prevention

of mice also results in the formation of ER-negative mammary tumors that exhibit a host of other genetic alterations similar to 

those seen in human breast carcinomas (Xu et al., 1999; Brodie et al., 2001; Weaver et al., 2002). This model has been used to 

demonstrate the efficacy of prophylactic oophorectomy for the prevention of breast cancer and is currently being used to test a 

wide range of chemopreventive agents (Deng et al., 2004).

Dietary Factors

Several epidemiological studies suggest an association between the consumption of certain dietary components and a reduction 

in breast cancer risk. The mechanisms by which these components confer chemoprotection are diverse (e.g., carcinogen 

metabolism, cell division, apoptosis, differentiation, and hormonal homeostasis) and have become the focus of numerous NCIsponsored research projects.

Various lines of evidence support the hypothesis that maintenance of a healthy body weight confers protection against 

postmenopausal breast cancer (Clinton et al., 1995). Moreover, a prospective population study found a significant positive 

linear trend in death rates for breast cancer with increasing body mass index (Calle et al., 2003). Although ecological and 

migrant studies usually demonstrate an association between fat intake and breast cancer, case-control and cohort studies have 

been inconsistent for this relationship (Kushi et al., 2002). In addition to quantity of fat consumed, the intake of specific fatty 

acids and duration of consumption may be involved in breast cancer (Rose, 1997). Interestingly, studies have identified several 

stages of a woman’s life in which the mammary glands may be particularly sensitive to dietary factors (i.e., fat), including the 

prenatal phase, puberty, and pregnancy (Hilakivi-Clarke et al., 1999; Baer et al., 2003; Hilakivi-Clarke et al., 1996). The 

production, metabolism, and bioavailability of sex hormones and their impact on target tissues may be responsible for these 

effects, and it has been documented that a high-fat diet increases levels of circulating estrogens, thereby potentially increasing 

the risk of breast cancer (Longcope et al., 1987). Research shows that women may be able to reduce their levels of two types of 

estrogens, estradiol and estrone, by consuming soy foods daily or, potentially, the isoflavone components genistein and diadzen 

(Kumar et al., 2002; Lu et al., 2001). Recent evidence suggests that the benefit from soy foods may be dependent on time of 

exposure, with childhood exposures offering greatest response (Wu et al., 2002; Shu et al., 2001).

The NCI has sponsored research on the mechanisms of chemoprevention by other natural products that are associated with a 

reduction in breast cancer risk. For example, the green tea polyphenol epigallocatechin-3 gallate has been found to inhibit cell 

growth via Her2/neu oncoprotein inhibition in mammary tumor cells (Pianetti at al., 2002). Furthermore, upregulation and 

stimulation of the vitamin D receptor by vitamin D, the polyphenol resveratrol (found in red wine) and the phytoestrogen 

genistein (found in soy) can suppress breast cancer cell growth (Welsh et al., 2003).

Prevention Trials

NCI-sponsored clinical trials in breast cancer prevention have led to an increased understanding of breast cancer risk factors 

and effective strategies for the reduction of disease incidence in pre- and postmenopausal women. Current clinical trials address 

strategies to prevent primary breast cancers in high-risk patients as well as secondary malignancies in breast cancer survivors.

Several clinical trials are addressing the use of SERMs for the prevention of breast cancer in high-risk women. The Breast 

Cancer Prevention Trial, conducted by the NSABP, revealed a 49% reduction in breast cancer incidence among the high-risk 

participants taking tamoxifen versus those taking a placebo (Fisher et al., 1998). Although women taking tamoxifen were at a 

slightly greater risk for endometrial cancer, they were at no greater risk for heart attack and had fewer bone fractures of the hip, 

wrist, and spine than women taking the placebo. In 1998, the FDA approved tamoxifen for use by high-risk women for breast 

cancer chemoprevention. As a follow-up, the NSABP is conducting the Study of Tamoxifen and Raloxifene (STAR) trial to 

determine if the osteoporosis prevention drug raloxifene can reduce breast cancer incidence as well as tamoxifen, but with fewer 

side effects, in high-risk postmenopausal women. Approximately 19,000 volunteers are participating in this trial at more than 

500 centers across the United States, Puerto Rico, and Canada.

Retinoids comprise another class of agents currently being investigated for breast cancer prevention. Retrospective analysis of 

data from one NCI-funded trial revealed that compared with untreated women, there were fewer second breast malignancies in 

premenopausal women, but not in postmenopausal women, randomized to the retinoid, fenretinide (Veronesi et al., 1999). In 
NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-11

addition, a significant decrease of circulating insulin-like growth factor (IGF)-1, a known risk factor for premenopausal breast 

cancer, was observed after 1 year of fenretinide administration in premenopausal women with breast cancer (Decensi et al., 

2001). These results, along with preclinical studies of new generations of retinoids, support the continued evaluation of these 

compounds for the prevention of breast cancer, particularly among premenopausal women.

Continuing Needs and Evolution

The above summary of initiatives and accomplishments indicates that much progress has been made, but additional knowledge 

is needed to further reduce the incidence of breast cancer. The Breast Cancer Prevention Trial of tamoxifen in women at 

increased risk of breast cancer showed a 49% overall reduction in breast cancers in women who took tamoxifen for 5 years. 

ER-positive, invasive breast cancer cases were reduced by 70%; however, the tamoxifen intervention had little impact on the 

incidence of ER-negative breast cancer. Thus, an intervention strategy that reduces the incidence of both ER-positive and 

ER-negative breast cancer is a priority. Such a result might be achieved by combining a SERM with a second agent. As noted 

above, a number of small trials using such combinations are in progress, and mechanistic studies are under way to delineate the 

targets of suppression for pathways involved in both ER-positive and ER-negative disease.

In addition to the focus on targeted interventions, more specific methods of identifying breast cancer risk would greatly 

enhance the efficiency of definitive Phase III prevention trials, which currently require large numbers of women to be followed 

for many years. It is possible for a woman to enter a large trial like STAR if her risk of developing breast cancer over the 5 years 

from entry is 1.7% or more. A more reliable method for identifying women at risk would facilitate the conduct of large trials 

by reducing the number of participants required to enroll in the study.

Work is also being directed to determine why some of the women who use preventive interventions like tamoxifen develop 

breast cancer in spite of the intervention. For those women who are identified as eligible for an intervention to reduce breast 

cancer risk, a further goal is to reliably identify the subset of women who are most likely to benefit from the intervention. 

Targeted agents with increased specificity are expected to reduce unnecessary intervention.

Finally, it is a focus of prevention research to identify specific modifications of lifestyle, such as changes in diet and exercise 

patterns, which can be used to reduce breast cancer risk throughout life. This approach allows intervention at a much earlier 

stage of breast development for longer periods of time, avoiding some of the toxicities and cost that accompany pharmacologic 

interventions that are likely to be used later in life.

NCI-Supported Research Referenced in Chapter 5

Baer HJ, Schnitt SJ, Connolly JL, Byrne C, Cho E, Willett WC, Colditz GA. Adolescent diet and incidence of proliferative 

benign breast disease. Cancer Epidemiol Biomarkers Prev. 2003 Nov;12 (11 Pt 1):1159-1167.

Brodie SG, Xu X, Qiao W, Li WM, Cao L, Deng CX. Multiple genetic changes are associated with mammary tumorigenesis in 

BRCA1 conditional knockout mice. Oncogene. 2001 Nov 8;20(51):7514-7523.

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively 

studied cohort of U.S. adults. N Engl J Med. 2003 Apr 24;348(17):1625-1638.

Clinton SK, Li PS, Mulloy AL, Imrey PB, Nandkumar S, Visek WJ. The combined effects of dietary fat and estrogen on 

survival, 7,12-dimethylbenz(a)anthracene-induced breast cancer and prolactin metabolism in rats. J Nutr. 1995 May;125(5):

1192-1204.

Decensi A, Johansson H, Miceli R, Mariani L, Camerini T, Cavadini E, Di Mauro MG, Barreca A, Gonzaga AG, Diani S, 

Sandri MT, De Palo G, Formelli F. Long-term effects of fenretinide, a retinoic acid derivative, on the insulin-like growth factor 

system in women with early breast cancer. Cancer Epidemiol Biomarkers Prev. 2001 Oct;10(10):1047-1053.

Deng CX, Xu X. Generation and analysis of Brca1 conditional knockout mice. Methods Mol Biol 2004;280:185-200.
October 2004 NCI Breast Cancer Progress Report

5-12 Chapter 5: Prevention

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins 

J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National 

Surgical Adjuvant Breast and Bowel Project P-1 Study. JNCI. 1998 Sep 16;90(18):1371-1388.

Herbert BS, Wright AC, Passons CM, Wright WE, Ali IU, Kopelovich L, Shay JW. Effects of chemopreventive and 

antitelomerase agents on the spontaneous immortalization of breast epithelial cells. JNCI. 2001 Jan 3;93(1):39-45.

Hilakivi-Clarke L, Clarke R, Lippman M. The influence of maternal diet on breast cancer risk among female offspring. 

Nutrition. 1999 May;15(5):392-401.

Hilakivi-Clarke L, Onojafe I, Raygada M, Cho E, Clarke R, Lippman ME. Breast cancer risk in rats fed a diet high in n-6 

polyunsaturated fatty acids during pregnancy. JNCI. 1996 Dec 18;88(24):1821-1827.

Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, Thaler HT, Muller WJ, Du B, Brown AM, Dannenberg 

AJ. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (Her-2)/neuinduced breast cancer. Cancer Res. 2002 Oct 1;62(19):5405-5407.

Kumar NB, Cantor A, Allen K, Riccardi D, Cox CE. The specific role of isoflavones on estrogen metabolism in premenopausal 

women. Cancer. 2002 Feb 15;94(4):1166-1174.

Kushi L, Giovannucci E. Dietary fat and cancer. Am J Med. 2002 Dec 30;113 Suppl 9B:63S-70S. Review.

Longcope C, Gorbach S, Goldin B, Woods M, Dwyer J, Morrill A, Warram J. The effect of a low fat diet on estrogen 

metabolism. J Clin Endocrinol Metab. 1987 Jun;64(6):1246-1250.

Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, Celestino J, Shen Q, Kim H, Hilsenbeck S, Mohsin SK, Wakeling A, 

Osborne CK, Brown PH. Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative 

mammary tumors. JNCI. 2003 Dec 17;95(24):1825-1833.

Lu LJ, Anderson KE, Grady JJ, Nagamani, M. Effects of an isoflavone-free soy diet on ovarian hormones in premenopausal 

women. J Clin Endocrinol Metab. 2001 Jul;86(7):3045-52.

Muller JW, Sinn E, Pattengale PK, Wallace R, Leder P. Single-step induction of mammary adenocarcinoma in transgenic mice 

bearing the activated c-neu oncogene. Cell. 1988 Jul 1;54 (1):105-114.

Pianetti S, Guo S, Kavanagh KT, Sonenshein GE. Green tea polyphenol epigallocatechin-3 gallate inhibits Her2/neu signaling, 

proliferation, and transformed phenotype of breast cancer cells. Cancer Res. 2002 Feb 1;62(3):652-655.

Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD. Normal human mammary epithelial cells 

spontaneously escape senescence and acquire genomic changes. Nature. 2001 Feb 1;409(6820):633-637.

Rose DP. Dietary fatty acids and cancer. Am J Clin Nutr. 1997 Oct;66(4 Suppl):998S-1003S. Review.

Shu XO, Jin F, Dai Q, Wen W, Potter JD, Kushi LH, Ruan Z, Gao YT, Zheng W. Soyfood intake during adolescence and 

subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev. 2001 May;10(5):483-488.

Veronesi U, De Palo G, Marubini E, Costa A, Formelli F, Mariani L, Decensi A, Camerini T, Del Turco MR, Di Mauro MG, 

Muraca MG, Del Vecchio M, Pinto C, D’Aiuto G, Boni C, Campa T, Magni A, Miceli R, Perloff M, Malone WF, Sporn MB. 

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. JNCI. 1999 Nov 

3;91(21):1847-1856.

Weaver Z, Montagna C, Xu X, Howard T, Gadina M, Brodie SG, Deng CX, Ried T. Mammary tumors in mice conditionally 

mutant for BRCA1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of 

genomic imbalances that is similar to human breast cancer. Oncogene. 2002 Aug 1;21(33):5097-5107.

Welsh J, Wietzke JA, Zinser GM, Byrne B, Smith K, Narvaez CJ. Vitamin D-3 receptor as a target for breast cancer 

prevention. J Nutr. 2003 Jul;133(7 Suppl):2425S-2433S.
 NCI Breast Cancer Progress Report October 2004

Chapter 5: Prevention 5-13

Wu AH, Wan P, Hankin J, Tseng CC, Yu MC, Pike MC. Adolescent and adult soy intake and risk of breast cancer in AsianAmericans. Carcinogenesis. 2002 Sep;23(9):1491-1496.

Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CX. Conditional mutation 

of BRCA1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet. 1999 

May;22(1):37-43.

NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-1

Chapter 6:

Early Detection, Diagnosis, and Prognosis of 

Breast Cancer: NCI’s Investment and Recent 

Progress

In the coming decade, we should strive to develop noninvasive methods for detecting and characterizing 

with certainty precancerous and cancerous breast lesions when they are small and more easily treated. 

Charting the Course: Priorities for Breast Cancer Research

Research has shown that early detection, in combination with effective treatment, can reduce mortality from breast cancer. The 

steady drop in breast cancer mortality rates since the early 1990s has, to a great extent, been due to improvements in screening 

and treatment. NCI is supporting research on early detection to improve the technologies and practices of early screening 

and minimize the invasiveness of procedures. Research on diagnosis and prognosis is aimed at improving the accuracy of 

predictions regarding the course of disease and selecting the most appropriate interventions.

Recent research supported by NCI has identified many novel biomarkers for breast cancer, as well as new imaging technologies 

that may enhance mammography or serve as alternatives to it. For example, to develop and evaluate the feasibility of novel 

image acquisition or enhancement methods, NCI has issued a program announcement, Development of Novel Imaging 

Technologies, and is sponsoring the Diagnostic Imaging Network–American College of Radiology Imaging Network (ACRIN), 

a multi-institution network for cooperative studies. In addition, the Institute’s Innovative Technologies for the Molecular 

Analysis of Cancer program supports the application of novel and emerging molecular analysis technologies in cancer research, 

including the identification of molecular markers. NCI’s Exploratory Studies in Cancer Detection, Prognosis, and Prediction 

are exploring innovative strategies for the early detection of cancer, assessment of cancer prognosis, or prediction of response to 

cancer treatment.

In its 1998 report, the Breast Cancer PRG identified nine priorities that deal with important research topics in early detection, 

diagnosis, and prognosis of breast cancer. Five of these priorities address the need in cancer imaging to: determine the potential 

of newer imaging technologies to better detect and diagnose clinically significant breast disease, determine whether computeraided technologies can further improve the interpretation of conventional mammography, identify the imaging characteristics 

of breast lesions detected by newer imaging technologies, develop standardized interpretation rules to identify these lesions 

using these modalities, determine whether early detection by any imaging modality truly changes the mortality from breast 

cancer, and develop new methods to diagnose clinically significant breast disease and predict clinical outcomes. Four of the 

PRG priorities focus on serum and tissue analyses: use tumor-specific biomarkers as functional imaging agents to improve the 

performance of imaging modalities; identify biomarkers that predict the clinical outcome of precancerous and cancerous breast 

lesions that are left untreated, as well as the response of precancerous and cancerous breast lesions to specific types of therapy; 

and interpret and use information on the complex phenotypes of breast lesions that involve abnormalities in many biomarkers 

simultaneously.

The NCI has been responsive to the PRG priorities related to the early detection, diagnosis, and prognosis of breast cancer. 

NCI-sponsored research has recently assessed the use of novel imaging technologies to serve as alternatives or adjuncts to 

mammography or to increase the sensitivity and specificity of mammography. Researchers have also identified numerous novel 

biologic markers that may serve as screening tests for the diagnosis and management of breast cancer, assess a patient’s risk of 

developing an initial or secondary breast cancer, and predict the probable course of the disease and whether it will respond to a 

given therapy. Additionally, recent reports prepared by the Breast Screening Working Group and the Breast Cancer Surveillance 

Consortium evaluated screening practices and presented ongoing challenges and future opportunities to improve breast cancer 

screening (see Chapter 8 for more details).
October 2004 NCI Breast Cancer Progress Report

6-2 Chapter 6: Early Detection, Diagnosis, and Prognosis

NCI’s Investment and 

Response

From FY1998 to 2003, NCI’s extramural investment in 

breast cancer early detection, diagnosis, and prognosis 

research increased from $36.4 million to $73.2 million 

(Figure 6-1). This increase corresponds to increases in the 

number of projects that are responsive to the nine Breast 

Cancer PRG research priorities for early detection, diagnosis, 

and prognosis summarized in Table 6-1.1

Table 6-1. NCI Efforts Responsive to PRG Priorities and Opportunities 

in Early Detection, Diagnosis, and Prognosisa

PRG Priority:

Determine the potential of newer imaging 

technologies (e.g., magnetic resonance 

imaging, positron emission tomography, digital 

mammography, mammoscintigraphy, sentinel 

lymph node localization/sampling, magnetic 

resonance elastography, electrical impedance 

imaging, microwave spectroscopy, and nearinfrared spectroscopy) to detect and diagnose 

clinically significant breast disease better than 

is currently done by physical examination and 

conventional mammography. 

NCI Efforts:

■ In FY2003, examples of active areas of investigation included positron emission tomography (PET) cameras with 

optimized geometry for detecting breast cancer or axillary node involvement, an integrated ultrasound and digital xray imaging system for screening and diagnostic mammography, breast cancer metabolic imaging with near-infrared 

light, and analytical solution techniques to improve magnetic resonance elastography.

■ Examples of clinical trials addressing this priority included the following:

◆ Comparison of Positron Emitter Iodine I 124 Iododeoxyuridine with Fludeoxyglucose F 18 (F-18 2-Fluoro-2-

Deoxy-(D)-Glucose) as Tracer for Glycolysis on Scans and in Tumor Samples in Patients With Advanced Breast 

Cancer (MSKCC-97046)

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars

Figure 6-1. NCI’s extramural investment in research on 

breast cancer early detection, diagnosis, and prognosis: 

1998-2003 (in millions of dollars)

1 A project may map to more than one PRG priority and therefore be represented in more than one figure. Projects active in 2003 are listed in Appendix B (Tables B-24 to 

B-32) by Principal Investigator’s name for each PRG priority.

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

a. Some of the original PRG priorities are addressed jointly in Table 6-1 because these priorities address partially overlapping issues and they are relevant to many of 

the same research projects and initiatives.
NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-3

◆ Diagnostic Study of Magnetic Resonance Imaging in Evaluating the Contralateral Breast of Women with a Recent 

Unilateral Diagnosis of Breast Cancer (ACRIN-6667)

◆ Randomized Screening and Diagnostic Study of Digital Mammography Versus Screen-Film Mammography in the 

Detection of Breast Cancer in Women (ACRIN 6652)

◆ Pilot Diagnostic Study of Fludeoxyglucose F 18 Positron Emission Tomography for Preoperative Evaluation of 

Women with Primary or Recurrent Breast Cancer (MSKCC-01134)

◆ Screening Study of Breast Imaging Outcome Measures and Phase of Menstrual Cycle in Women at High Genetic 

Risk of Breast Cancer (NCI-01-C-0008)

■ On September 26, 2002, NCI sponsored the Third Inter-Institute Workshop on Diagnostic Optical Imaging and 

Spectroscopy: The Clinical Adventure. On February 6-7, 2003, NCI sponsored the 4th National Forum on Biomedical 

Imaging in Oncology.

■ NCI initiatives addressing this priority included the Bioengineering Research Grants, Breast Specialized Programs 

of Research Excellence (SPOREs), Cancer Imaging Program (CIP), Development of Novel Technologies for In Vivo 

Imaging, and Diagnostic Imaging Network—American College of Radiology Imaging Network (ACRIN).

PRG Priority:

Can computer-aided technologies further 

improve the interpretation of conventional 

mammography? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included studies to improve and 

test the performance and robustness of several 

computer-aided diagnosis (CAD) schemes 

for mammography; a content-based search 

engine that displays lesions of known pathology, making artificial neural network (ANN) output more reliable for 

computer processing; and CAD methodology for extracting information related to the spatial structure of the breast 

from ipsilateral views.

■ Examples of clinical trials addressing this priority included the following:

◆ Randomized Screening and Diagnostic Study of Digital Mammography Versus Screen-Film Mammography in the 

Detection of Breast Cancer in Women (ACRIN-6652)

◆ Screening and Diagnostic Study of Magnetic Resonance Imaging in Women with Suspected Breast Cancer 

(UPCC-ACR-6884)

◆ Diagnostic Study of Magnetic Resonance Imaging in Women With Suspected Breast Tumors (UPCC-ACR-6883).

■ On September 26, 2002, NCI sponsored the Third Inter-Institute Workshop on Diagnostic Optical Imaging 

and Spectroscopy: The Clinical Adventure. On February 6-7, 2003, NCI sponsored the 4th National Forum on 

Biomedical Imaging in Oncology

■ NCI initiatives addressing this priority included the Cancer Imaging Program, Development of Novel Technologies 

for In Vivo Imaging, Diagnostic Imaging Network—American College of Radiology Imaging Network (ACRIN), and 

Exploratory/Developmental Grants for Diagnostic Cancer Imaging.

0

5

10

15

20

25

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

6-4 Chapter 6: Early Detection, Diagnosis, and Prognosis

PRG Priority:

What are the imaging characteristics of specific types 

of benign and malignant breast lesions detected 

by newer imaging technologies? Can standardized 

interpretation rules be developed to identify these 

lesions for any of these modalities? Can they 

replace or augment conventional mammography in 

screening general or high-risk populations? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included computer models that combine mammography and breast ultrasound findings to identify breast 

masses that are probably benign; a unilateral method of obtaining rapid dynamic and high-spatial-resolution, contrastenhanced breast MRI data; the integration of gray-scale ultrasound and Doppler imaging to diagnose breast cancers; 

and the use of thermal information as an adjunct to mammography for equivocal mammography results.

■ Examples of clinical trials addressing this priority included the following:

◆ Radiolabeled 99mTechnetium-Dextran (99Tcm-Dextran) With Isosulfan Blue Prior to Resection of the Sentinel 

Lymph Node in Breast Cancer Patients (UCLA-HSPC-960629301)

◆ Diagnostic Study of Positron Emission Tomography in Patients With Stage II-IV or Recurrent Breast Cancer 

(NCI-94-C-0151)

◆ Pilot Screening Study of Breast Imaging Outcome Measures in Women at High Genetic Risk of Breast Cancer 

(NCI-01-C-0009)

■ On February 6-7, 2003, NCI sponsored the 4th National Forum on Biomedical Imaging in Oncology.

■ NCI initiatives addressing this priority included the Cancer Imaging Program (CIP), the Cancer Research Network 

(CRN), and Diagnostic Imaging Network—American College of Radiology Imaging Network (ACRIN).

PRG Priority:

Can tumor-specific biomarkers be identified and used 

as imaging agents to improve the performance of any 

imaging modality?b

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included near-infrared-emitting, fluorochromeconjugated metabolite probes capable of imaging 

in vivo metabolic function in real time, monitoring 

tumor neovascularity using contrast-enhanced 

ultrasound imaging modes, estrogens labeled with 

fluorine-18 and carbon-11 as imaging agents for estrogen receptor-positive tumors, and near-infrared-fluorescent 

contrast agents and optical imaging for sentinel lymph node mapping in vivo.

0

5

10

15

20

25

30

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

4

8

12

16

20

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

b The priority was changed from the original “Can tumor-specific biomarkers be identified and used as contrast agents to improve the performance of any imaging 

modality?”
NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-5

■ NCI initiatives addressing this priority incl;uded the Cancer Imaging Program (CIP), the Cancer Research Small 

Grant Program, the Early Detection Research Network, and In Vivo Cellular and Molecular Imaging Centers 

(ICMICs).

PRG Priority:

Does early detection by any imaging modality 

truly change the mortality from breast cancer? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included several long-term data 

collection and linkage efforts to measure 

the accuracy and outcomes of screening 

mammography.

■ The NCI initiative addressing this priority was the International Breast Cancer Screening Network (IBSN).

PRG Priority:

Develop new methods to diagnose clinically significant 

breast disease and predict clinical outcomes better 

than conventional histologic examination and the 

few available biomarker assays (e.g., S-phase fraction, 

estrogen receptor, progesterone receptor, and c-erbB-2). 

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included radiolabeled gastrin-releasing, peptide 

receptor-avid radiopharmaceuticals as site-directed agents to treat and/or diagnose patients with breast cancer; a novel 

DNA chip for high-throughput analysis of promoter hypermethylation in primary tumors; microchip electrophoresis 

technologies for molecular detection of cancer by tandem single-strand conformational polymorphism/heteroduplex 

analysis; and multimarker, real-time reverse transcriptase-polymerase chain reaction (RT-PCR) detection of breast 

cancer cells in lymph nodes of breast cancer patients to detect metastases.

■ Examples of clinical trials addressing this priority included the following:

◆ Diagnostic Randomized Study of Radioactive Seed Localized Breast Biopsy Versus Needle Localized Breast Biopsy in 

Patients with Nonpalpable Breast Lesions (MCC-12114)

◆ Pilot Study to Evaluate the Incidence of Clonal Hematopoiesis as a Marker of Genetic Damage Following Adjuvant 

Chemotherapy for Stage II/III Breast Cancer (SWOG-S9719)

■ On January 7-8, 2002, NCI sponsored a workshop, Detection and Measurement of Occult Disease for the Prognosis of 

Solid Tumors, to identify priorities for new clinical studies.

■ NCI initiatives addressing this priority included Applications of Innovative Technologies for the Molecular Analysis of 

Cancer; the Breast SPOREs; Cancer Prognosis and Prediction; Clinical Proteomics Program (CPP); Early Detection 

Research Network; Exploratory Studies in Cancer Detection, Prognosis, and Prediction; Exploratory/Developmental 

Grants for Diagnostic Cancer Imaging; Cancer Diagnosis Program; and Program for the Assessment of Clinical 

Cancer Tests.

0

4

8

12

16

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

0

10

20

30

40

50

60

70

80

90

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

6-6 Chapter 6: Early Detection, Diagnosis, and Prognosis

PRG Priorities:

Are there biomarkers that predict the clinical outcome of 

precancerous and cancerous breast lesions if left untreated 

(i.e., prognostic factors) with a high degree of certainty? 

(STR-B)

Are there biomarkers that predict the response of 

precancerous and cancerous breast lesions to specific types 

of therapy (i.e., predictive factors) with a high degree of 

certainty? (STR-C)

NCI Efforts:

■ In FY2003, examples of active areas of investigation relevant to the following priorities included:

◆ Both STR-B and STR-C: the development of markers of apoptosis and cell proliferation, a probe for accurate 

sentinel node localization without the need for the radioactive technetium tracer, in vivo measurements of tumor 

metabolism to predict and evaluate response to therapy, a comprehensive gene expression profile to compare sets 

of lymph node-negative breast cancer, and an evaluation of the perinucleolar compartment as a prognostic and 

predictive tumor marker.

◆ STR-B: the angiogenesis status in invasive ductal carcinoma of the breast by immunohistochemistry and magnetic 

resonance imaging (MRI), changes in the apparent diffusion coefficient of tissue water in response to chemotherapy 

as a marker for apoptosis, and probes as imaging agents for the epidermal growth factor receptor (EGFR).

◆ STR-C: cancer chemoprevention by a set of phytochemicals, quantitative analysis of the expression of the molecule 

Her2/neu on breast tissue biopsies, and a functional cloning strategy to identify Taxol resistance-inducing genes.

■ Examples of clinical trials addressing these priorities included the following:

◆ Diagnostic Study of Contrast-Enhanced Magnetic Resonance Imaging and Correlative Molecular Studies in Women 

With Locally Advanced Breast Cancer Who Are Receiving Neoadjuvant Chemotherapy (CALGB-150007)

■ On October 14-16, 2001, NCI’s Cancer Biomarkers Research Group sponsored the 2nd Annual Scientific Workshop 

of the Early Detection Research Network (EDRN). On January 7-8, 2002, NCI sponsored a workshop, Detection and 

Measurement of Occult Disease for the Prognosis of Solid Tumors, to identify priorities for new clinical studies.

■ NCI initiatives addressing this priority included the Breast SPOREs; Cancer Prognosis and Prediction; Clinical 

Proteomics Program (CPP); Early Detection Research Network; Exploratory Studies in Cancer Detection, Prognosis, 

and Prediction; Cancer Diagnosis Program; and Program for the Assessment of Clinical Cancer Tests.

PRG Priority:

Premalignant and malignant breast lesions often have 

complex phenotypes involving abnormalities in many 

biomarkers simultaneously. How do we interpret and 

use this information? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included imaging probes for the 

in vivo sensing of specific proteases, molecular 

0

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40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

STR-B STR-C

0

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20

30

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NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-7

diagnostic tests for breast cancer, prognostic modeling for patients with high-risk primary breast cancer, and assays 

using expression-based markers to detect circulating breast cancer cells.

■ Examples of clinical trials addressing these priorities included the following:

◆ Diagnostic and Genetic Study of Breast Duct Lavage, Breast Duct Endoscopy, and DNA Gene Expression Profiling 

in Women With Ipsilateral Breast Cancer Versus Healthy Women Who Are Not at High Risk for Breast Cancer 

(NCI-02-C-0077B)

◆ Phase II Pilot Study of cDNA Microarray as a Measure of Tumor Response to Neoadjuvant Docetaxel and 

Capecitabine Followed by Surgery and Adjuvant Doxorubicin and Cyclophosphamide in Patients With Stage II or 

III Breast Cancer (NCI-00-C-0149)

■ On October 14-16, 2001, NCI’s Cancer Biomarkers Research Group sponsored the 2nd Annual Scientific Workshop 

of the Early Detection Research Network (EDRN). On January 7-8, 2002, NCI sponsored a workshop, Detection and 

Measurement of Occult Disease for the Prognosis of Solid Tumors, to identify priorities for new clinical studies.

■ NCI initiatives addressing this priority included the Breast SPOREs; Cancer Prognosis and Prediction; Clinical 

Proteomics Program (CPP); Early Detection Research Network; Exploratory Studies in Cancer Detection, Prognosis, 

and Prediction; Cooperative Breast Cancer Tissue Resource; Cancer Diagnosis Program; Program for the Assessment 

of Clinical Cancer Tests; and Director’s Challenge: Toward a Molecular Classification of Tumors.

Additional Breast Cancer Early Detection, 

Diagnosis, and Prognosis Projects

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included biological markers of breast 

cancer and tamoxifen response; mammaglobin, a 

breast-specific gene, as a marker for the detection 

of breast cancer; a diagnostic device that measures 

optical and electrical properties of tissue near the 

tip of a 20-gauge needle probe; and an integrated 

model of disease history linked to submodels portraying modifiable points in the cancer control process, including 

early detection and methods to enhance diagnosis.

The initiatives relevant to research on breast cancer early detection, diagnosis, and prognosis between FY1998 and 2003 

include the following list of general initiatives that are described in Table 2-12 (Chapter 2) and the category-specific initiatives 

that are listed and described in Table 6-2:3

■ Aging Women and Breast Cancer

■ Applications of Innovative Technologies for the Molecular Analysis of Cancer

■ Bioengineering Research Grants

■ Bioengineering Research Partnerships

0

10

20

30

40

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1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

2 Initiatives that impact multiple categories of breast cancer research.

3 Initiatives that are unique to the early detection, diagnosis, and prognosis research category.
October 2004 NCI Breast Cancer Progress Report

6-8 Chapter 6: Early Detection, Diagnosis, and Prognosis

■ Breast and Ovarian Cancer Family Registries (CFRs)

■ Breast Cancer Faculty

■ Breast Cancer Surveillance Consortium (BCSC)

■ Cancer Biomedical Informatics Grid (caBIG)

■ Cancer Centers Program

■ Cancer Genome Anatomy Project (CGAP) 

■ Cancer Imaging Program (CIP)

■ Cancer Molecular Analysis Project (CMAP)

■ Cancer Prognosis and Prediction

■ Cancer Research Network (CRN)

■ Cancer Research Small Grant Program

■ Cancer Research Training, Career Development, and Education Opportunities 

■ Clinical Trials Cooperative Group Program 

■ Cooperative Breast Cancer Tissue Resource (CBCTR)

■ Cooperative Human Tissue Network (CHTN) 

■ Correlative Studies Using Specimens From Multi-Institutional Treatment Trials

■ Director’s Challenge: Toward a Molecular Classification of Tumors

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

■ Improving DNA, RNA and Protein Availability in Fixed Tissue 

■ Insight Awards to Stamp Out Breast Cancer

■ Integrating Aging and Cancer Research

■ Interdisciplinary Research Teams for Molecular Target Assessment 

■ International Breast Cancer Screening Network

■ In Vivo Cellular and Molecular Imaging Centers (ICMICs)

■ Minority Institution/Cancer Center Partnership (MI/CCP) 

■ NCI Center for Bioinformatics (NCICB) 

■ Program for Assessment of Clinical Cancer Tests (PACCT)

■ Shared Pathology Informatics Network (SPIN)

■ Shared Resources for Scientists Outside NCI Cancer Centers 

■ Small Animal Imaging Resource Program (SAIRP) 

■ Small Grants Program for Cancer Epidemiology

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer

■ Specimen Resource Locator
NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-9

■ Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors

■ Therapeutic Modulation of Angiogenesis in Disease

■ Unconventional Innovations Program (UIP)

Table 6-2. NCI Initiatives Relevant to Breast Cancer Research: Early Detection, Diagnosis, and Prognosisa

Initiatives Relevant to Breast Cancer Research

■ Development of Digital Mammography Displays and Workstations (PA-99-082; PA-99-083)

◆ Overview: Supports advances in the state of the art in digital mammography displays and workstation design to 

obtain the full potential of digital mammography for improved breast cancer diagnosis.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, five projects relevant to breast cancer 

research were supported through this PA. One of these projects was active in 2003 and can be found in Appendix B, 

Table B24, by searching for the PA number.

Initiatives with Breast Cancer-Relevant Components

■ Cancer Diagnosis Program (http://www.cancerdiagnosis.nci.nih.gov/)

◆ Overview: Stimulates and supports diagnostics research, resources, and improved technologies to guide the choice of 

treatment for cancer patients.

◆ Relevant Projects Resulting From This Initiative:

Breast Cancer Diagnosis: Blood-Cell Multigene Signatures

The Perinucleolar Compartment as Breast Cancer Marker

Multimarker Detection of Breast Metastases in PET Nodes

Prognostic Modeling of High-Risk Primary Breast Cancer

■ Clinical Proteomics Program (CPP) (http://ncifdaproteomics.com/index.php)

◆ Overview: Facilitates the invention, development, and employment of proteomic technologies for translational 

bench-to-bedside cancer treatment applications. CPP is supported by both the NCI and U.S. Food and Drug 

Administration.

◆ Relevant Technologies Resulting From This Initiative: The CPP strives to improve early cancer detection 

technologies and develop new approaches to more effectively determine product safety, potency, and purity. Two 

exciting new technologies have been developed:

Reverse-Phase Protein Microarrays for Signal Pathway Profiling and Phosphoproteomics

Serum Proteomic Pattern Diagnostics for Blood-Based Detection of Cancer

■ Development of Clinical Imaging Drug Enhancers (DCIDE) (http://www3.cancer.gov/bip/DCID_des.htm)

◆ Overview: Expedites and facilitates the development of promising investigational imaging enhancers (contrast 

agents) or molecular probes from the laboratory to Investigational New Drug status.

◆ Relevant Products Resulting From This Initiative: New imaging reagents for PET and MRI detection of tumor 

angiogenesis are being evaluated.

a. Lists of the projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiative Database.
October 2004 NCI Breast Cancer Progress Report

6-10 Chapter 6: Early Detection, Diagnosis, and Prognosis

■ Development of Novel Technologies for In Vivo Imaging (PAR-01-101; PAR-01-102)

◆ Overview: Facilitates the development of novel imaging technologies for early detection, screening, diagnosis, or 

image-guided treatment of cancer and environmentally induced disease, as well as clinical evaluation studies that are 

limited to proof of concept.

◆ Relevant Research Projects Resulting From These PAs: Between 1998 and 2003, 27 projects relevant to breast cancer 

research were supported through these PAs. Specific projects can be found in Appendix B, Tables B24-B27, B29, 

B30, and B33, by searching for these and the previously issued PA numbers (PAR-00-089 and PAR-00-090).

■ Diagnostic Imaging Network–American College of Radiology Imaging Network (ACRIN) (http://www.acrin.org/)

◆ Overview: Facilitating cooperative studies in diagnostic imaging. ACRIN is a multi-institutional network that 

is developing productive interfaces with industrial sources of new imaging technologies and has the capacity to 

perform pilot studies and randomized, controlled trials to assess the value of imaging innovations in the practice of 

oncology.

◆ Relevant Clinical Trials Resulting From This Initiative: Current clinical protocols are published on the ACRIN Web 

site and include four breast cancer trials:

Contrast-Enhanced Breast MRI for Evaluation of Patients Undergoing Neoadjuvant Treatment for Locally Advanced 

Breast Cancer

Digital Versus Film-Screen Mammography

MRI Evaluation of the Contralateral Breast in Women With a Recent Diagnosis of Breast Cancer

Screening Breast Ultrasound in High-Risk Women

■ Early Detection Research Network (EDRN) (http://www3.cancer.gov/prevention/cbrg/edrn)

◆ Overview: Collaboratively develops and tests promising biomarkers and technologies, with rapid dissemination 

of results. The consortium currently includes: 18 biomarker development laboratories, with 4 that address breast 

cancer; 3 biomarker validation laboratories; 9 clinical and epidemiologic centers, with 1 that addresses breast cancer, 

and a single data management and coordinating center. The EDRN organization includes a Breast and Gynecologic 

Cancer Collaborative Group.

◆ Relevant Projects Resulting From This Initiative: Between 1998 and 2003, six projects relevant to breast cancer 

research were supported through this initiative. Specific projects can be found in Appendix B, Tables B2, B7, B9, 

B15, and B29-B31, by searching for the RFA number (RFA-CA-98-028).

■ Exploratory/Developmental Grants for Diagnostic Cancer Imaging (PA-01-030)

◆ Overview: Supports highly innovative research concepts in diagnostic cancer imaging.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, 35 projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B24-B27, B29, and 

B33, by searching for this PA number and the previously issued PA number (PA-98-008).

■ Exploratory Studies in Cancer Detection, Prognosis and Prediction (PA-03-003)

◆ Overview: Promotes the initial evaluation of molecular or cellular characteristics in human specimens and/or the 

development of assays that may result in important advances in the detection, diagnosis, and treatment of cancers.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, eight projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B2, B4, B7, B9, B15, 

B29-B31, and B36, by searching for the PA number and the previously issued PA number (PA-01-010).
NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-11

■ Exploratory Studies in Cancer Diagnostics (PA-98-022)

◆ Overview: Provides support for research to identify novel molecular or cellular abnormalities in tumors that will be 

useful for cancer diagnosis.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, nine projects relevant to breast cancer 

research were supported through this PA.b

■ Gene Expression Data Portal (GEDP) (http://gedp.nci.nih.gov/dc/index.jsp)

◆ Overview: Facilitates microarray research through publicly available online data annotation and analysis tools and 

stores microarray data for sharing with the research community.

◆ Relevant Research Products Maintained through This Initiative: Relevant data are available for the following research 

areas:

Multiclass Cancer Diagnosis Using Tumor Gene Expression Signatures

Initiating Oncogenic Event Determines Gene-Expression Patterns Of Human Breast Cancer Models

Initiating Oncogenic Events Determines Gene-Expression Patterns Of Breast Cancer Models–C3(1)/SV40Tag

Initiating Oncogenic Events Determines Gene-Expression Patterns Of Breast Cancer Models–MMTV-c-myc

Initiating Oncogenic Events Determines Gene-Expression Patterns Of Breast Cancer Models–MMTV-HA-ras

Initiating Oncogenic Events Determines Gene-Expression Patterns Of Breast Cancer Models–MMTV-neu

Initiating Oncogenic Events Determines Gene-Expression Patterns Of Breast Cancer Models–MMTV-PyMT

Initiating Oncogenic Events Determines Gene-Expression Patterns Of Breast Cancer Models–WAP-SV40(Tag)

Secretory Activation in Wild-Type Mice From Preg12 to Lac9

■ Innovative Technologies for the Molecular Analysis of Cancer (PAR-01-105; PAR-01-104)

◆ Overview: Supports development of novel technologies for the molecular analysis of cancers and their host 

environment through basic, clinical, and epidemiological research.

◆ Relevant Research Projects Resulting From These PAs: Between 1998 and 2003, 34 projects relevant to breast cancer 

research were supported through these PAs. Specific projects can be found in Appendix B, Tables B1-B3 and B29-

B32, by searching for these and the previously issued PA numbers (PAR-98-066, PAR-98-067, PAR-99-100, and 

PAR-99-101).

■ Tissue Array Research Program (TARP) (http://ccr.cancer.gov/tech_initiatives/tarp)

◆ Overview: Develops and disseminates Multi-Tumor Tissue Microarray slides and related technology to cancer 

research investigators.

◆ Relevant Resource Resulting From This Initiative: TARP distributes a Breast and Ovarian Cancer Array containing 

65 well-annotated breast adenocarcinoma samples that can be used for immunofluorescence, in situ hybridization, 

immunohistochemistry, and histochemistry applications. Related protocols are also available on the TARP Web site.

b. Lists of the projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiative Database.
October 2004 NCI Breast Cancer Progress Report

6-12 Chapter 6: Early Detection, Diagnosis, and Prognosis

Ongoing NCI Research: Recent Progress in Breast Cancer Early 

Detection, Diagnosis, and Prognosis

Imaging Technologies

Breast cancer screening and detection methods have improved as technological advances have occurred. Novel imaging devices 

are now available in digital formats that can be read, analyzed, stored, and shared by health care providers.

One alternative to mammography that is currently being investigated is PET, a molecular imaging method that provides 

information on a tumor’s biology using radioactive tracers to evaluate viability and glucose metabolism (using fluoro-deoxyglucose [FDG]), oxygen status, and estrogen receptor status. In a recent prospective multicenter study on the role of FDG-PET 

in axillary node staging, researchers found that FDG-PET is moderately accurate for detecting axillary metastasis although 

false-negative axillae resulted from nodal metastases being smaller and fewer in number than true-positive axillae (Wahl et al., 

2004). PET techniques are being used to evaluate the changes in blood flow and metabolism in locally advanced breast cancer 

following neoadjuvant therapy (Mankoff et al., 2003). PET has also been used for detecting increased tumor uptake of FDG 

to predict whether patients with estrogen receptor (ER)-positive metastatic breast cancer will respond to antiestrogen therapy 

(Dehdashti et al., 1999).

Another technology, MRI, is being used increasingly to characterize suspicious breast lesions detected on mammography and 

to monitor response to therapy. Although contrast-enhanced MRI has high sensitivity, its signal characteristics are not quite 

specific for cancer. Researchers are therefore exploring the possibility of developing and using a tissue signature method for 

identification and classification of normal and abnormal breast tissue (Jacobs et al., 2003). The use of MRI to evaluate response 

of breast cancer to hormonal therapy is also under investigation (Bogin and Degan, 2002). Furthermore, researchers are using 

streptavidin-conjugated superparamagnetic nanoparticles as targeted MR functional imaging agents to conduct cellular studies 

of the Her2/neu receptor, which plays a significant role in staging and treating breast cancer (Artemov et al., 2003).

Computers are being used as analytic and knowledge-enhancing tools to improve the diagnostic accuracy of breast imaging. For 

example, investigators have evaluated the effectiveness of a convolution neural network (CNN) optimized with an automated 

technique to improve the accuracy of a microcalcification detection computer program, in comparison with manually selected 

CNN. The sensitivity for the optimized CNN was 93%, compared with 87% for the manually selected CNN. The authors 

concluded that an optimized CNN can reduce false-positive findings and improve the accuracy of a computer-aided detection 

system (Gurcan et al., 2002).

Investigators have also analyzed an automated estimation analysis tool to estimate mammographic breast density (Zhou et 

al., 2001). The computer misclassified only 6% of the breast regions and produced highly accurate results for the remaining 

mammograms. This technique might be useful for estimating risk or for monitoring breast density changes in prevention or 

intervention programs.

Biologic Markers

As a result of powerful new molecular technologies, studies of biologic markers have significantly increased. Biologic markers 

have been detected in human serum, breast nipple aspirate fluid, and tissue samples. The following NCI-supported research 

represents examples of biologic markers for breast cancer that may become clinically useful.

The mammaglobin gene encodes a 10 kDa glycoprotein, and in normal adult tissues, mammaglobin mRNA expression has 

been detected only in the mammary gland. Researchers found that 80% of all primary and metastatic breast tumors were 

strongly immunopositive for mammaglobin protein, and staining was independent of tumor grade (Fleming and Watson, 

2000). When researchers used a monoclonal antibody-based assay to monitor the presence of mammaglobin in serum, they 

found elevated levels in sera of patients with breast cancer compared to the sera of healthy women (Fanger et al., 2002). These 

results indicate that mammaglobin protein and mRNA in clinical samples might be useful markers for primary, metastatic, and 

occult breast cancer and that mammaglobin might provide a rapid screening test for the diagnosis and management of breast 

cancer.
NCI Breast Cancer Progress Report October 2004

Chapter 6: Early Detection, Diagnosis, and Prognosis 6-13

The epidermal growth factor receptor (EGFR) family of growth factor receptor tyrosine kinases includes EGFR and ErbB-2, 

which is overexpressed in about one-third of breast cancers. ErbB-2 and EGFR may mediate motility through signaling that 

enables changes in the actin cytoskeleton, and this motility may depend on the coexpression of gelsolin, an actin-binding 

protein. When the expression of ErbB-2, EGFR, and gelsolin was analyzed in archival invasive breast cancers, researchers found 

that tumor gelsolin was associated with overexpression of ErbB-2 and EGFR, as well as an aggressive tumor phenotype (Thor 

et al., 2001). Gelsolin coexpression might be an important prognostic factor in patients with ErbB-2-positive, EGFR-negative 

breast cancer.

2,6-cyclolycopene-1,5-diol is the major oxidation product of lycopene in human serum. Researchers used high-performance 

liquid chromatography with electrochemical detection to quantify 2,6-cyclolycopene-1,5-diol and lycopene in plasma and 

breast nipple aspirate fluid (NAF). Levels of 2,6-cyclolycopene-1,5-diol and 8-isoprostane (a marker of lipid oxidation) were 

higher in NAF than in plasma and are consistent with high levels of oxidative stress in the breast (Chen and Djuric, 2002). 

Therefore, oxidized lycopene metabolites may serve as markers of oxidative stress.

Combinations of markers are now proving to be stronger predictors of recurrence than single markers. Examination of gene 

expression using cDNA microarrays has resulted in the identification of clusters of expressed genes that are associated with 

different types of breast tumors (Perou et al., 2000) and with risk of recurrence (Sorlie et al., 2001). These data have been used 

to develop an RT-PCR-based test that generates a risk score (Paik et al., 2003), and the Breast Intergroup is preparing to test 

this risk score prospectively in a large Phase III trial.

Research on novel biomarkers now offers the possibility of predicting which patients with ER-positive breast cancer will 

respond to tamoxifen, an important systemic treatment for this type of cancer. One study has shown that pretreatment 

levels of ER significantly predicted response to tamoxifen treatment; by multivariate analysis, it was associated with 27 times 

the likelihood of response (Chang et al., 2000). Another study showed that high expression levels of AIb1 (SRC-3), an ER 

coactivator, in patients not receiving adjuvant tamoxifen therapy was associated with better prognosis and longer disease-free 

survival, while high AIb1 expression in patients receiving tamoxifen therapy was associated with worse disease-free survival, 

indicating tamoxifen resistance (Osborne et al., 2003). Thus, AIb1 might be an important diagnostic and therapeutic target.

Continuing Needs and Evolution

Screening film mammography has the best sensitivity and specificity of any existing breast cancer screening tool, but it still 

needs refinement. In addition, several technologies are being examined for their role in breast cancer detection and diagnosis. 

For example, researchers are advancing computer-aided diagnostic methods in the hope of improving their reproducibility 

for consistently accurate diagnosis of breast cancer. Investigations are continuing to assess the utility of MRI for finding 

small breast lesions that may be missed in mammograms, producing better images of dense or augmented breast tissue, and 

helping with treatment staging and follow-up. Additional biomarkers are being identified for the various stages of breast 

cancer development, and research is addressing their potential for risk assessment, screening, and diagnosis. As more and better 

markers are discovered, it may become possible to develop bioassays that can detect the presence of breast cancer or precancer 

and predict its clinical course.

NCI-Supported Research Referenced in Chapter 6

Artemov D, Mori N, Okollie B, Bhujwalla ZM. MR molecular imaging of the Her2/neu receptor in breast cancer cells using 

targeted iron oxide nanoparticles. Magn Reson Med. 2003 Mar;49(3):403-408.

Bogin L, Degani H. Hormonal regulation of VEGF in orthotopic MCF7 human breast cancer. Cancer Res. 2002 Apr 1;62(7):

1948-1951.

Chang J, Powles TJ, Allred DC, Ashley SE, Makris A, Gregory RK, Osborne CK, Dowsett M. Prediction of clinical outcome 

from primary tamoxifen by expression of biologic markers in breast cancer patients. Clin Cancer Res. 2000 Feb;6(2):616-621.
October 2004 NCI Breast Cancer Progress Report

6-14 Chapter 6: Early Detection, Diagnosis, and Prognosis

Chen G, Djuric Z. Detection of 2,6-cyclolycopene-1,5-diol in breast nipple aspirate fluids and plasma: a potential marker of 

oxidative stress. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1592-1596.

Dehdashti F, Flanagan FL, Mortimer JE, Katzenellenbogen JA, Welch MJ, Siegel BA. Positron emission tomographic 

assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med. 1999 

Jan;26(1):51-56.

Fanger GR, Houghton RL, Retter MW, Hendrickson RC, Babcook J, Dillon DC, Durham MD, Reynolds LD, Johnson JC, 

Carter D, Fleming TP, Roche PC, Persing DH, Reed SG. Detection of mammaglobin in the sera of patients with breast cancer. 

Tumour Biol. 2002 Jul-Aug;23(4):212-221.

Fleming TP, Watson MA. Mammaglobin, a breast-specific gene, and its utility as a marker for breast cancer. Ann N Y Acad Sci. 

2000;923:78-89.

Gurcan MN, Chan HP, Sahiner B, Hadjiiski L, Petrick N, Helvie MA. Optimal neural network architecture selection: 

improvement in computerized detection of microcalcifications. Acad Radiol. 2002 Apr;9(4):420-429.

Jacobs MA, Barker PB, Bluemke DA, Maranto C, Arnold C, Herskovits EH, Bhujwalla Z. Benign and malignant breast 

lesions: diagnosis with multiparametric MR imaging. Radiology. 2003 Oct;229(1):225-232.

Mankoff DA, Dunnwald LK, Gralow JR, Ellis GK, Schubert EK, Tseng J, Lawton TJ, Linden HM, Livingston RB. Changes 

in blood flow and metabolism in locally advanced breast cancer treated with neoadjuvant chemotherapy. J Nucl Med. 2003 

Nov;44(11):1806-1814.

Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM, Schiff R. Role 

of the estrogen receptor coactivator AIB1 (SRC-3) and Her2/neu in tamoxifen resistance in breast cancer. JNCI. 2003 Mar 

5;95(5):353-361.

Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner R, Walker M, Watson D, Park T, Bryant J, Wolmark N. Multigene RT-PCR assay for predicting recurrence in node negative breast cancer patients—NSABP studies B-20 and B-14. Breast 

Cancer Res Treat. 2003;82 (Supp. 1):S10.

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, 

Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of 

human breast tumours. Nature. 2000 Aug 17;406(6797):747-752.

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen 

T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL. Gene expression patterns of breast 

carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-

10874.

Thor AD, Edgerton SM, Liu S, Moore DH 2nd, Kwiatkowski DJ. Gelsolin as a negative prognostic factor and effector of 

motility in erbB-2-positive epidermal growth factor receptor-positive breast cancers. Clin Cancer Res. 2001 Aug;7(8):2415-

2424.

Wahl RL, Siegel BA, Coleman RE, Gatsonis CG; PET Study Group. Prospective multicenter study of axillary nodal staging 

by positron emission tomography in breast cancer: a report of the staging breast cancer with PET Study Group. J Clin Oncol. 

2004 Jan 15;22(2):277-285.

Zhou C, Chan HP, Petrick N, Helvie MA, Goodsitt MM, Sahiner B, Hadjiiski LM. Computerized image analysis: estimation 

of breast density on mammograms. Med Phys. 2001 Jun;28(6):1056-1069.
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-1

Chapter 7:

Breast Cancer Treatment: NCI’s Investment and 

Recent Progress

The goal of breast cancer treatment research is to dramatically improve management and outcome of 

all stages of the disease. Charting the Course: Priorities for Breast Cancer Research

Research leading to improved cancer treatment plays a prominent role in NCI’s cancer portfolio. Treatment research aims to 

identify and exploit the most promising areas of science and technology to yield important new information that will lead to 

better therapeutic interventions. It spans activities ranging from discovery of new interventions in the laboratory, to preclinical 

testing of safety and efficacy in animal models, to phased clinical trials in cancer patients.

In its 1998 report, the Breast Cancer PRG identified several goals for treatment research that, if met, would dramatically 

improve the management and outcome of all stages of breast disease. These goals included increasing disease-free and overall 

survival, improving patient outcomes, lowering the incidence of secondary breast cancers, and improving access to the highestquality medical care for all Americans. The PRG recognized that achieving these endpoints would require improvement in 

several areas and outlined five priorities in breast cancer treatment research that could guide this effort. For both localized and 

advanced breast cancer, the PRG stressed the importance of:

■ Developing innovative biological approaches for the treatment of breast cancer

■ Developing the expertise required for modern clinical investigation

■ Facilitating the design and conduct of large-scale clinical trials

■ Learning more about breast cancer biology to better predict the clinical course of disease and response to therapy

■ Increasing public access to information regarding treatment options and clinical trials

The NCI has been responsive to these PRG priorities. In the years since the release of the PRG report, the NCI has supported a 

wide range of research projects, training programs, and clinical trials that address these treatment-related priorities. As a result, 

there has been an increase in the number of effective therapeutic drugs in clinical practice, the number of ongoing breast cancer 

clinical trials testing new agents, and the rate of patient accrual to these clinical trials. One of the most notable advancements 

over the past 5 years in breast cancer treatment has been the shift in focus from using high-dose systemic chemotherapy 

regimens to the development of targeted therapies that are more effective and less toxic. The field of targeted therapeutics was 

pioneered by the monoclonal antibody-based drug, trastuzumab (Herceptin®), which was approved in 1998 for treatment of 

Her2-overexpressing metastatic breast cancer. In the ensuing years, several other classes of novel anticancer drugs and targeted 

delivery systems, including aromatase inhibitors and immunoliposomal vehicles, have been developed and are currently 

undergoing preclinical and clinical testing. In 1999, the aromatase inhibitor exemestane (Aromasin®) was approved for the 

treatment of breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy, making it the 

fourth aromatase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer.

Since the release of the 1998 PRG report, NCI has sponsored a major report that is relevant to recommendations of the Breast 

Cancer PRG for treatment. The report, National Institutes of Health Consensus Development Conference Statement: Adjuvant 

Therapy for Breast Cancer, November 1–3, 2000,

1

 summarizes currently available data on the use of adjuvant therapy for breast 

cancer. A 14-member panel developed conclusions based on evidence presented by experts in medical oncology, radiation 

oncology, biostatistics, epidemiology, surgical oncology, and clinical trials. The panel concluded that women should only 

receive adjuvant hormonal therapy if their tumors express hormone-receptor protein. Most women with localized breast cancer 

should receive adjuvant polychemotherapy, regardless of lymph node, menopausal, or hormone-receptor status, because it 

 1 Published in the Journal of the National Cancer Institute. 2001 Jul 4;93(13):979-89.
October 2004 NCI Breast Cancer Progress Report

7-2 Chapter 7: Treatment

improves survival. The panel also pointed to the critical need for trials to evaluate the role of adjuvant chemotherapy in women 

older than 70 years and the impact of its side effects on quality of life.

NCI’s Investment and 

Response

From FY1998 to 2003, the NCI’s extramural investment 

in research on breast cancer treatment has increased 

from $52.0 million to $108.2 million (Figure 7-1). 

This increase in funding corresponds to increases in the 

number of projects that are responsive to PRG priorities 

in treatment research.

Table 7-1 summarizes the NCI’s responsiveness to the five 

Breast Cancer PRG research priorities for treatment. In addition, 

NCI’s responsiveness to one of the original PRG priorities on 

breast cancer genetics is summarized in Table 7-1.2

Table 7-1. NCI Efforts Responsive to PRG Priorities and Opportunities in Treatment

PRG Priority:

How can we develop innovative biological 

approaches to the treatment of breast cancer, in 

the laboratory and via small (pilot) trials? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the association of a 

novel gene (wth3) with multidrug resistance; 

specific immunotherapy with monoclonal 

antibodies; novel cytotoxic products derived from marine sponges; biosynthesis of maytansinoids and analogs; drug 

discovery by mirror image ligand display; combinatorial creation of new anticancer agents; synthesis of WS9885B, 

a novel cytotoxic tubulin binder; novel therapeutic uses of phenylacetate in breast cancer; stress-induced bystander 

effects in cancer treatment; and preclinical evaluation of a novel apoptosis-inducing antitumor agent (MX2060).

■ Examples of clinical trials addressing this priority included the following:

◆ Phase I Pilot Study of Her2/neu Intracellular Domain Protein-Pulsed Autologous Dendritic Cells in Patients With 

Her2/neu Expressing Advanced Malignancies Showing No Evidence of Disease After Standard Treatment 

(DUMC-1309-00-7R1

◆ Phase I Study of LMB-9 Immunotoxin in Patients With Advanced Colon, Breast, Non-Small Cell Lung, Bladder, 

Pancreas, or Ovarian Cancer (MSGCC-9981)

◆ Phase I/II Randomized Study of Monoclonal Antibody CAL Versus Zoledronate in Women With Breast Cancer and 

Bone Metastases (CWRU-080235)

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars

0

50

100

150

200

250

300

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

Figure 7-1. NCI’s extramural investment in breast 

cancer treatment research:

1998-2003 (in millions of dollars)

2 A project may map to more than one PRG priority and therefore be represented in more than one figure. Projects active in 2003 are listed in Appendix B (Tables B-33 to 

B-39) by Principal Investigator’s name for each PRG priority.
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-3

◆ Pilot Phase II study of sequential PANVAC-VF followed by the addition of docetaxel in metastatic breast cancer 

(LOI 6977 approved)

◆ Pilot Study to Evaluate Angiogenesis After Treatment With Bevacizumab (Anti-VEGF Humanized Monoclonal 

Antibody) in Previously Untreated Patients With Inflammatory Breast Cancer or Locally Advanced Breast Cancer 

(01-C-0173)

◆ Phase II Randomized Study of Anastrozole and Gefitinib Versus Fulvestrant and Gefitinib in Postmenopausal 

Women With Recurrent or Metastatic Hormone Receptor-Positive Breast Cancer (ECOG-4101)

◆ Phase Ib/II Neoadjuvant Study of Tipifarnib, Docetaxel, and Capecitabine in Patients With Locally Advanced or 

Metastatic Solid Tumors or Stage IIIA or IIIB Breast Cancer (NCI-5599)

■ On September 28-29, 1999, NCI sponsored the first biannual National Cancer Institute-Cancer Therapy Evaluation 

Program (CTEP) Drug Development Meeting. On January 31-February 1, 2001, NCI Sponsored the Workshop on 

Potential Clinical Applications for GnRH Antagonists. On October 5–6, 2000, NCI sponsored a meeting on Novel 

Molecular Targets for Cancer Therapy.

■ NCI initiatives addressing this priority included the Specialized Program of Research Excellence (SPORE) in Breast 

Cancer, Cancer Drug Discovery: Diversity Generation and Smart Assays, Cancer Therapy-Related Use of Genetically 

Engineered Mice, Clinical Proteomics Program (CPP), Exploratory Grants for Correlative Laboratory Studies and 

Clinical Trials, Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses 

(FLAIR), Molecular Target Drug Discovery for Cancer, National Cooperative Drug Discovery Groups (NCDDGs), 

Quick Trials for Novel Cancer Therapies, Rapid Access to Intervention Development (RAID) Program, Rapid Access 

to NCI Discovery Resources (RAND), Therapeutic Modulation of Angiogenesis in Disease, and Unconventional 

Innovations Program (UIP).

PRG Priority:

How can we facilitate the design and conduct of 

large clinical trials in breast cancer, focusing on 

the endpoints of longer disease-free and overall 

survival, reduced treatment toxicity, reduced breast 

cancer incidence, and ease of delivery to the entire 

population (including rural patients, the elderly, 

the economically disadvantaged, and members of 

minority groups)?

NCI Efforts:

■ In FY2003, examples of active areas of investigation included enhancing Native American participation in 

radiotherapy trials, understanding barriers to enrolling the elderly in cancer trials, evaluating cancer disparities among 

Hispanic communities, adjuvant hormonal therapy for Vietnamese women with breast cancer, simultaneous thermoradiotherapy for breast carcinoma, and numerous trials conducted at clinical oncology program centers.

■ Examples of clinical trials addressing this priority included the following:

◆ Correlation of Menstrual Cycle Phase at the Time of Surgery With Disease-Free Survival in Premenopausal Women 

With Stage I or II Breast Cancer (NCCTG-N9431)

◆ Phase III Randomized Study of Paclitaxel via One-Hour Infusion Every Week Versus 3-Hour Infusion Every 3 

Weeks With or Without Trastuzumab (Herceptin®) in Women With Inoperable, Recurrent, or Metastatic Breast 

Cancer With or Without Overexpression of Her2/neu (CLB-9840)

0

25

50

75

100

125

150

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

7-4 Chapter 7: Treatment

◆ Phase III Prognostic Study of Sentinel Node and Bone Marrow Micrometastases in Women With Stage I or IIA 

Breast Cancer (ACOSOG-Z0010)

◆ Phase III Randomized Study of Neoadjuvant Docetaxel and Carboplatin With Versus Without Trastuzumab 

(Herceptin®) in Women With Locally Advanced Breast Cancer (UCLA-9911084)

◆ Phase III Randomized Study of Four Schedules of Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in 

Patients With Node-Positive or High-Risk Node-Negative Breast Cancer (SWOG-S0221)

◆ Phase III Randomized Study of Letrozole Versus Placebo in Postmenopausal Women With Primary Breast Cancer 

Who Have Completed at Least Five Years of Adjuvant Tamoxifen (MA.17)

◆ Phase III Randomized Study of Sequential Chemotherapy Using Doxorubicin, Paclitaxel, and Cyclophosphamide 

or Concurrent Doxorubicin and Cyclophosphamide Followed by Paclitaxel at 14 and 21 Day Intervals in Women 

With Node-Positive Stage II or IIIA Breast Cancer (CALGB-9741).

■ NCI initiatives addressing this priority included the Cancer Trials Support Unit (CTSU), Clinical Trials Cooperative 

Group Program, Community Clinical Oncology Program (CCOP), Cooperative Planning Grant for Cancer 

Disparities Research Partnership, Expanded Participation Project (EPP), and Minority-Based Community Clinical 

Oncology Program (MBCCOP).

PRG Priority:

How can we develop the expertise required for modern 

clinical investigation? 

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included a physician-scientist training program 

for clinical investigation protocol development, 

role of Her4 as a differentiation factor in breast 

cancer, clinical research in stem cell transplantation, 

education and training of surgical oncologists in the biologic basis of cancer and translational research, continued 

funding for a quality assurance review center, training physician-scientists to develop specific targets for therapy based 

on genetic and epigenetic alterations in cancer cells, semi-parametric and empirical process methods in oncology, 

urban Latino and African-American cancer disparities project, and a workshop on the nuclear radiology of breast 

cancer.

■ On November 1-3, 2000, NCI sponsored the Adjuvant Therapy for Breast Cancer-National Institutes of Health (NIH) 

Consensus Development Conference. On April 26-28, 2000, NCI sponsored the NIH Selective Estrogen Receptor 

Modulators (SERMs) Workshop. On October 5-6, 2000, NCI sponsored Novel Molecular Targets for Cancer Therapy.

■ The Center for Cancer Research at NCI provides training programs for postdoctoral fellows that focus on translational 

research projects in clinical oncology, cultural sensitivity training, and scientific management training.

■ The recently introduced cancer Biomedical Informatics Grid (caBIG) is addressing some of these issues by assembling 

basic and clinical informatics tools that can be used widely by the cancer research community. In addition, caBIG is 

supporting the development of new tools by biomedical researchers.

■ NCI initiatives addressing this priority included Breast SPOREs; Cancer Research Training, Career Development and 

Education Opportunities; Shared Resources for Scientists Outside NCI Cancer Centers; Special Populations Networks 

(SPNs); and Translational Research Initiative (TRI). 

0

10

20

30

40

50

60

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-5

PRG Priority:

How can we learn more about the biology of 

breast cancer for the purpose of predicting clinical 

course and predicting response to therapy?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included evaluation of biologic 

endpoints and pharmacokinetics in patients 

with metastatic breast cancer after treatment 

with erlotinib, protein kinase C as a marker in tamoxifen-resistant breast cancer, defective estrogen receptors in 

breast tumors, the role of proteinase-3 in apoptosis and drug resistance, identification of paclitaxel-resistance genes, 

understanding how glutathione-s-transferase (GST) synergizes with the MRP toxin efflux transporter in multidrug 

resistance, and genetic modulation of cellular radiation responses.

■ On December 4-5, 2003, NCI sponsored the Linking Haplotypes and Genetic Variation With Cancer Risk Assessment, 

Prevention, Detection, and Treatment Workshop.

■ Clinical trials and related programs addressing this priority include:

◆ Phase II Pilot Study of cDNA Microarray as a Measure of Tumor Response to Neoadjuvant Docetaxel and 

Capecitabine Followed by Surgery and Adjuvant Doxorubicin and Cyclophosphamide in Patients With Stage II or 

III Breast Cancer (NCI-00-C-0149)

◆ Program for the Assessment of Clinical Cancer Tests (PACCT)

■ NCI initiatives addressing this priority included the Cancer Molecular Analysis Project (CMAP), Cancer Prognosis 

and Prediction, and the Cooperative Human Tissue Network (CHTN).

PRG Priority:

Access to accurate information on treatment 

options, including available clinical trials, is critical 

for patients, their families, and providers.

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the Urban Latino 

African-American Cancer Disparities Project, 

education and collaboration to enhance breast 

cancer care, the Partnership to Increase Hispanic 

Cancer Research Education, breast cancer patients’ treatment preferences, enhancing Native American participation 

in radiotherapy trials, training minority scientists in research, overcoming barriers to early-phase clinical trials, 

educational and outreach approaches for cancer prevention, and improving cancer outcomes for African Americans.

■ On August 27-29, 2003, NCI cosponsored the Trans-HHS Cancer Health Disparities Progress Review Group 

Roundtable.

■ NCI resources that provide information about various types of cancer treatment options, including available clinical 

trials, include the Cancer Information Service (CIS), the NCI Publications Locator, and caMATCH, a computerized 

system for matching breast cancer patients with trials.

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

10

20

30

40

50

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
October 2004 NCI Breast Cancer Progress Report

7-6 Chapter 7: Treatment

■ NCI initiatives addressing this priority included the cancer Biomedical Informatics Grid (caBIG), Community 

Clinical Oncology Program (CCOP), Expanded Participation Project (EPP), Minority-Based Community Clinical 

Oncology Program (MBCCOP), Special Populations Networks (SPNs), and the Cancer Trials Support Unit.

PRG Priority:

Are different recommendations for extent of surgery 

or reconstruction appropriate for women with an 

inherited predisposition?a

NCI Efforts:

■ In FY2003, an active area of investigation was 

the national prospective study of risk-reducing 

salpingo-oophorectomy and ovarian screening 

among women at increased genetic risk of breast 

and ovarian cancer.

■ NCI-funded researchers participate in the Prevention and Observation of Surgical End Points (PROSE) study group, 

an international clinical outcomes collaboration addressing the effectiveness of surgery on women with inherited 

predisposition to breast cancer.

■ NCI initiatives addressing this priority included the Cancer Genetics Network (CGN) and Cancer Genetics Services 

Directory.

Additional Breast Cancer Treatment Projects

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included percutaneous removal and margin ablation 

for breast cancer; induction of cell cycle arrest by 

clotrimazole—an inhibitor of RNA translation 

initiation; the role of the acetyltransferase p300 in 

cellular responses; p21 transcriptional inhibitors as 

proapoptotic compounds; healing touch, immunity, 

and fatigue in breast cancer; grp78 and hypersensitivity 

to DNA cross-linking agents; and interleukin-10 for breast cancer therapy.

■ Clinical trials and related programs addressing this priority include:

◆ Phase II Randomized Study of Metronomic Low-Dose Cyclophosphamide and Methotrexate With or Without 

Bevacizumab in Women With Metastatic Breast Cancer (DFCI-03083).

■ Research in the emerging area of image-guided therapies included magnetic resonance (MR) methods for guiding 

thermal therapy, anatomic and biologic staging of breast disease with MRI, integrated ultrasonic systems for 

noninvasive therapy, and MR-guided surgery and radiation therapy.

a. This priority was part of the Genetics section in the original Breast Cancer PRG report.

0

5

10

15

20

25

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

1

2

3

4

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-7

Clinical trials comprised a large part of the NCI’s responsiveness to PRG priorities related to breast cancer treatment. A 

search of the Physician’s Data Query Clinical Trials database for NCI-sponsored breast cancer treatment protocols identified 

nearly 300 clinical trials that were active between 1998 and 2003.3 More than 130 of these trials were Phase I or Phase II 

investigations of innovative biological approaches for breast cancer treatment, and another 55 were large-scale clinical trials.

The initiatives that impacted breast cancer treatment research between 1998 and 2003 include the following list of general 

initiatives that are described in Table 2-1,4 as well as the category-specific initiatives described in Table 7-2.5

■ Aging Women and Breast Cancer

■ Applications of Innovative Technologies for the Molecular Analysis of Cancer

■ Basic and Preclinical Research on Complementary Alternative Medicine

■ Bioengineering Research Grants

■ Bioengineering Research Partnerships

■ Breast and Ovarian Cancer Family Registries

■ Breast Cancer Faculty

■ Cancer Biomedical Informatics Grid (caBIG)

■ Cancer Centers Program

■ Cancer Imaging Program (CIP) 

■ Cancer Molecular Analysis Project (CMAP)

■ Cancer Prognosis and Prediction

■ Cancer Research Training, Career Development, and Education Opportunities 

■ Clinical Trials Cooperative Group Program 

■ Community Clinical Oncology Program (CCOP)

■ Cooperative Breast Cancer Tissue Resource (CBCTR)

■ Cooperative Human Tissue Network (CHTN)

■ Correlative Studies Using Specimens From Multi-Institutional Treatment Trials

■ Developmental/Pilot Projects in Cancer Complementary and Alternative Medicine

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

■ Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses (FLAIR) 

■ Insight Awards to Stamp Out Breast Cancer

■ Integrating Aging and Cancer Research

■ Interdisciplinary Research Teams for Molecular Target Assessment

■ In Vivo Cellular and Molecular Imaging Centers (ICMICs) 

3 An NCI-sponsored clinical trial in the Physician Data Query (PDQ) database meets one or more of the following criteria: the protocol (1) has been reviewed and approved 

by NCI’s CTEP Protocol Review Committee or by an approved NCI-designated Cancer Center Protocol Review and Monitoring System; and/or (2) receives support 

through an NCI grant or cooperative agreement. Information on ongoing treatment trials for the different stages of breast cancer can be obtained via the NCI’s Clinical 

Trials Web page. To limit a search to only those trials that are sponsored by the NCI, it is necessary to use the advanced search function.

4 Initiatives that impact multiple categories of breast cancer research.

5 Initiatives that are unique to the treatment chapter.
October 2004 NCI Breast Cancer Progress Report

7-8 Chapter 7: Treatment

■ Minority Institution/Cancer Center Partnership (MI/CCP)

■ Minority-Based Community Clinical Oncology Program (MBCCOP)

■ Molecular Target Drug Discovery for Cancer

■ NCI Center for Bioinformatics (NCICB)

■ Nonmammalian Organisms as Models for Anticancer Drug Discovery

■ Program for the Assessment of Clinical Cancer Tests (PACCT)

■ Shared Pathology Informatics Network (SPIN)

■ Shared Resources for Scientists Outside NCI Cancer Centers 

■ Small-Animal Imaging Resource Program (SAIRP)

■ Small Grants Program in Cancer Epidemiology

■ Special Populations Networks (SPNs)

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer

■ Specimen Resource Locator 

■ Therapeutic Modulation of Angiogenesis in Disease

■ Unconventional Innovations Program (UIP)

Table 7-2. NCI Initiatives Relevant to Breast Cancer Research: Treatmenta

Initiatives With Breast Cancer-Relevant Components

■ Cancer Drug Discovery: Diversity Generation and Smart Assays (RFA-CA-98-009)

◆ Overview: Supports multidisciplinary teams of chemists and biologists who propose novel approaches to discover 

classes of compounds with potential anticancer activity.

◆ Relevant Projects Resulting From This RFA: Between 1998 and 2003, two projects relevant to breast cancer research 

were supported through this RFA. Specific projects can be found in Appendix B, Table B33, by searching for the 

current RFA number and the previously issued RFA number (RFA-97-006).

■ Cancer Therapy-Related Use of Genetically Engineered Mice (PAR-02-051)

◆ Overview: Supports the use of genetically engineered mouse models for cancer therapy-related goals.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, one project relevant to breast cancer 

research was supported through this PA:

Transgenic Mice as Models for Antivascular Therapy

■ Cancer Trials Support Unit (CTSU) (http://www.ctsu.org)

◆ Overview: Supports a national network of physicians to participate in NCI-sponsored Phase III clinical trials. 

Cooperative Clinical Trials Group sites within the United States and Canada are eligible for participation in the 

CTSU. In addition, the CTSU is now open to physicians and institutions in the United States that are not affiliated 

with a Cooperative Group.

a Lists of the projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiative Database.
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-9

◆ Relevant Clinical Protocols Resulting From This Initiative: Current CTSU-listed protocols for breast cancer include:

Phase III Randomized Study of Axillary Lymph Node Dissection in Women With Stage I or IIA Breast Cancer Who 

Have a Positive Sentinel Node (ACOSOG-Z0011)

Phase III Randomized Study of Adjuvant Cyclophosphamide and Doxorubicin Versus Paclitaxel in Women With 

Node-Negative Breast Cancer (CALGB-40101)

Phase III Randomized Trial of Adjuvant Chemotherapy Comprising Standard Cyclophosphamide, Methotrexate, 

and Fluorouracil (CMF) or Doxorubicin and Cyclophosphamide (AC) Versus Oral Capecitabine in Elderly Women 

With Operable Adenocarcinoma of the Breast (CALGB-49907)

Phase III Randomized Study of Paclitaxel With or Without Bevacizumab in Patients With Locally Recurrent or 

Metastatic Breast Cancer (ECOG-2100)

Phase III Randomized Study of Ovarian Function Suppression in Combination With Tamoxifen Versus Ovarian 

Function Suppression in Combination With Exemestane Versus Tamoxifen Alone in Premenopausal Women With 

Endocrine-Responsive Breast Cancer (IBCSG-24-02)

Phase III Randomized Study of Triptorelin and Exemestane Versus Triptorelin and Tamoxifen in Premenopausal 

Women With Endocrine-Responsive Breast Cancer (IBCSG-25-02)

Phase III Randomized Study of Ovarian-Function Suppression and Tamoxifen or Exemestane With Versus Without 

Adjuvant Chemotherapy in Premenopausal Women With Endocrine-Responsive Resected Breast Cancer 

(IBCSG-26-02)

Phase III Randomized Study of Adjuvant Breast Radiotherapy With or Without Regional Radiotherapy in Women 

With Previously Resected, Early-Stage Invasive Breast Cancer (CAN-NCIC-MA20)

Phase III Randomized Study of Adjuvant Cyclophosphamide, Epirubicin, and Fluorouracil Versus 

Cyclophosphamide, Epirubicin, Filgrastim (G-CSF), and Epoetin Alfa Followed by Paclitaxel Versus 

Cyclophosphamide and Doxorubicin Followed by Paclitaxel in Premenopausal or Early Postmenopausal Women 

With Previously Resected Node-Positive or High-Risk Node-Negative Stage I-IIIB Breast Cancer 

(CAN-NCIC-MA21)

Phase III Randomized Adjuvant Study of Exemestane Versus Anastrozole With or Without Celecoxib in 

Postmenopausal Women With Receptor-Positive Primary Breast Cancer (CAN-NCIC-MA27)

Phase III Randomized Study of Adjuvant Doxorubicin and Cyclophosphamide Followed by Docetaxel Versus 

Doxorubicin and Docetaxel Versus Doxorubicin, Docetaxel, and Cyclophosphamide in Women With Breast Cancer 

and Positive Axillary Lymph Nodes (NSABP-B-30)

Phase III Randomized Study of Adjuvant Clodronate With or Without Systemic Chemotherapy and/or Tamoxifen 

in Women With Early-Stage Breast Cancer (NSABP-B-34)

Phase III Randomized Study of Anastrozole Versus Tamoxifen in Postmenopausal Women With Ductal Carcinoma 

In Situ of the Breast Undergoing Lumpectomy and Radiotherapy (NSABP-B-35)

Phase III Randomized Study of Whole-Breast Radiotherapy Versus Observation With or Without Optional 

Tamoxifen in Women With Good-Risk Ductal Carcinoma In Situ of the Breast (RTOG-9804)

Phase III Randomized Study of Standard Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Weekly 

Paclitaxel Versus Weekly Doxorubicin and Daily Oral Cyclophosphamide With Filgrastim (G-CSF) Followed by 

Weekly Paclitaxel in Women With Inflammatory or Locally Advanced Breast Cancer (SWOG-S0012)
October 2004 NCI Breast Cancer Progress Report

7-10 Chapter 7: Treatment

Phase III Randomized Study of Four Schedules of Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in 

Patients With Node-Positive or High-Risk Node-Negative Breast Cancer (SWOG-S0221)

■ Central Institutional Review Board (CIRB) (http://www.ncicirb.org/)

◆ Overview: Supports an innovative approach to human subjects protection through a “facilitated review” process 

that can streamline local Institutional Review Board (IRB) reviews of national multicenter cancer treatment trials. A 

pilot project is currently sponsored by the NCI in consultation with the Department of Health and Human Services 

Office of Human Research Protections.

◆ Relevant Results From This PA: Ten Cooperative Group-sponsored treatment protocols relevant to breast cancer 

have been approved by the CIRB since its inception in 2001.

■ Clinical Cancer Therapy Research (PA-02-002)

◆ Overview: Supports the translation of clinical cancer research insights and the development of new agents into 

innovative cancer therapeutic studies.

◆ Relevant Projects Resulting From This PA: Between 1998 and 2003, four projects relevant to breast cancer research 

were supported through this PA. Specific projects can be found in Appendix B, Tables B6 and B33, by searching for 

the current PA number and the previously issued PA numbers (PA-99-046 and PA-92-069).

■ Cooperative Planning Grant for Cancer Disparities Research Partnership (RFA-CA-03-018)

◆ Overview: Supports the planning, development, and conduct of radiation oncology clinical research trials in 

institutions that care for a disproportionate number of medically underserved, low-income, ethnic, and minority 

populations but have not been traditionally involved in NCI-sponsored research.

◆ Relevant Projects Resulting From This RFA: Between 1998 and 2003, five projects relevant to breast cancer research 

were supported through this RFA. Specific projects can be found in Appendix B, Tables B34, B35, B37, B45, and 

B51, by searching for the current RFA number and the previously issued RFA number (RFA-CA-02-002).

■ Development and Application of Imaging in Therapeutic Studies (RFA-CA-98-024)

◆ Overview: Supports research projects that apply imaging technologies in the assessment of investigational cancer 

therapeutic agents.

◆ Relevant Projects Resulting From This RFA: Between 1998 and 2003, two projects relevant to breast cancer research 

were supported through this RFA.b

■ Expanded Participation Project (EPP) (http://spitfire.emmes.com/study/epp)

◆ Overview: Supports a demonstration project for providing broader access to Cooperative Group Phase III trials for 

breast and three other cancer types.

◆ Relevant Programs Resulting From This Initiative: Twenty-eight participating institutions have centralized access to 

data from nine closed Phase III clinical trials on breast cancer.

■ National Cooperative Drug Discovery Groups (NCDDGs) (http://dtp.nci.nih.gov/branches/gcob/gcob_web3.html)

◆ Overview: Supports broad, innovative, multidisciplinary approaches to the discovery of new synthetic or natural 

source-derived anticancer drugs.

◆ Relevant Projects Resulting From This Initiative: Between 1998 and 2003, six projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Table B33, by searching for 

the RFA numbers RFA-CA-99-010, RFA-CA-95-020, and RFA-CA-94-007.

b Lists of the projects derived from initiatives can be found on the online Supplement to the Breast Cancer Progress Report: Initiative Database.
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-11

■ Quick Trials for Novel Cancer Therapies (PAR-03-005)

◆ Overview: Supports the rapid development of new therapeutic approaches and the assessment of these agents in 

pilot, Phase I, and Phase II cancer clinical trials through an accelerated review and funding process.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, 11 projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B24, B26, B33, B36, 

B39, and B51, by searching for the current PA number and the previously issued PA numbers (PA-00-047 and PA99-070).

■ Rapid Access to Intervention Development (RAID) Program (http://dtp.nci.nih.gov/docs/raid/raid_index.html)

◆ Overview: Supports the translation of novel, scientifically meritorious therapeutic interventions from the academic 

community to the clinic.

◆ Relevant Research Projects Resulting From This Initiative: Descriptions of RAID projects that have reached 

completion are available on the RAID Web site. To date, two breast cancer-relevant projects have been completed:

A Study of Safety and Immunological Response of Immunotherapy in Patients With Solid Tumors

Chemo-Immunotherapy for Metastatic Breast Cancer Treatment

■ Rapid Access to NCI Discovery Resources (RAND) (http://dtp.nci.nih.gov/docs/rand/rand_index.html)

◆ Overview: Supports academic and nonprofit investigators in the discovery of small molecules, biologics, or natural 

products with the potential for anticancer activity through such mechanisms as the development of high-throughput 

screening assays, computer modeling, recombinant target protein production and characterization, and chemical 

library generation.

◆ Relevant Project Resulting From This Initiative: One project funded in the latest program cycle is using an MMTVneu mouse model of breast cancer to screen for indoleamine 2,3-dioxygenase (IDO) inhibitors that mediate tumor 

regression.

■ Translational Research Initiative (TRI) (http://ctep.cancer.gov/resources/trf-overview.html)

◆ Overview: Supports correlative studies performed during the conduct of sponsored clinical trials of CTEP 

Investigational New Drug (IND) agents.

◆ Relevant Programs Resulting From This Initiative: The TRI supports translational studies using samples from 

patients who participate in Phase I and Phase II clinical trials. Among the TRI-approved and/or supported 

protocols, the following are examples of clinical trials open exclusively to breast cancer patients:

A Phase I Study of GTI-2040 and Capecitabine in the Treatment of Metastatic Breast Cancer

A Phase Ib/II Neoadjuvant Trial of R115777 With Docetaxel and Capecitabine for Patients With Stage IIIA or IIIB 

Breast Cancer

A Phase I-II Study of R115777 (Zarnestra) Plus Doxorubicin and Cyclophosphamide in Patients With Locally 

Advanced Breast Cancer and Metastatic Breast Cancer (P5598)

A Phase I Study of Epothilone B Analog (BMS-247550) in Combination With Carboplatin in Recurrent and/or 

Refractory Solid Tumors

A Phase II Trial of Primary Therapy With Bevacizumab and Docetaxel for Locally Advanced Breast Cancer

Phase II Study of Neoadjuvant Doxorubicin, Docetaxel, and Bcl-2 Antisense (Genasense) Therapy for Patients With 

Locally Advanced Breast Cancer

Phase II Trial of STI571 in Metastatic Breast Cancer
October 2004 NCI Breast Cancer Progress Report

7-12 Chapter 7: Treatment

A Phase II Study of Depsipeptide in Patients With Metastatic Breast Cancer

A Phase II Study of Perifosine in Patients With Metastatic or Advanced Breast Cancer

Vaccination With Breast Cancer/Dendritic Cell Fusions in Conjunction With IL-12

Ongoing NCI Research: Progress in Breast Cancer Treatment

Progress in Preclinical Models

Recent advances in the development of transgenic mouse models displaying aspects of breast cancer disease progression have 

led to changes in the way promising therapeutic agents are tested. NCI-supported scientists have developed a transgenic 

mouse model of mammary cancer by expressing recombinant simian virus 40 early-region transforming sequences under the 

regulatory control of the rat prostatic steroid-binding protein [C3(1)] gene. This strain of mice, termed C3(1)/SV40 Tag, 

spontaneously develop tumors of the mammary epithelium without hormone supplementation or pregnancy (Maroulakou et 

al., 1994). Tumor progression in these mice follows a predictable time course and replicates several important stages that occur 

during human breast cancer progression, including noninvasive carcinoma, invasive carcinoma, and metastasis to bone. These 

mice provide good preclinical models for testing therapeutic compounds and have been used to demonstrate the effectiveness 

of several promising agents, including:

■ Endostatin, which was shown to delay mammary tumor onset, inhibit the “angiogenic switch,” and decrease tumor burden 

in these mice (Calvo et al., 2002).

■ IL-12/pulse IL-2 treatment, which led to complete regression of established mammary carcinoma and prevented 

neovascularization in developing lesions (Wigginton et al., 2001), and 2-difluoromethylornithine (DFMO) and 

dehydroepiandrosterone (DHEA) combination, which was shown to inhibit mammary tumor progression in these mice 

(Green et al., 2001).

In Situ Disease

In situ breast disease—viewed as either noninvasive breast cancer or a precancerous condition—was an uncommon diagnosis 

until the widespread adoption of screening mammography. In 1998, about 18% of all new breast cancer diagnoses in the 

United States were identified as ductal carcinoma in situ (DCIS). Because a subset of DCIS patients goes on to develop breast 

cancer in the absence of treatment, the NCI has sponsored research on optimal treatment of in situ disease.

Although it was long thought that there was no role for postoperative therapy in the treatment of in situ disease, results from 

the B-24 trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP)—an NCI-funded clinical 

trials cooperative group—revealed that postsurgical tamoxifen is effective at preventing both invasive and noninvasive cancers 

in the ipsilateral (same) and contralateral (opposite) breasts of women with DCIS who have undergone breast conservation 

surgery followed by radiation (Fisher et al., 1999). In June 2000, the FDA approved tamoxifen (Nolvodex®)—an antiestrogen 

compound—as a postsurgical treatment for preventing invasive breast cancer in individuals with DCIS.

The NSABP B-35 trial is currently under way to determine whether postoperative anastrazole—a compound that prevents 

synthesis of estrogen by inhibiting the enzyme aromatase—is more effective than tamoxifen in preventing subsequent 

breast cancers in postmenopausal women with DCIS (Phase III Randomized Study of Anastrozole Versus Tamoxifen in 

Postmenopausal Women with Ductal Carcinoma In Situ of the Breast Undergoing Lumpectomy and Radiotherapy).

Operable Disease

Operable breast cancer, encompassing node-negative Stage I and Stage II disease and node-positive Stage II and Stage IIA 

disease, has traditionally been treated by a multimodal approach that includes surgery with or without subsequent radiation 

therapy for local control and, when deemed appropriate, postsurgical adjuvant hormonal and/or chemotherapy for systemic 
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-13

control. NCI-sponsored researchers are attempting to refine all aspects of the traditional treatment paradigm: the specific 

treatments that are deemed appropriate, the order in which the treatments are administered, the duration and doses at which 

the treatments are administered, and the specific agents that are administered.

It has long been known that patients with operable node-positive disease are at higher risk for breast cancer recurrence than 

patients with node-negative disease and that node-negative patients with large tumors are at higher risk than those with small 

tumors. In the past, adjuvant therapy was not considered necessary for the majority of patients with node-negative breast 

cancers. The combined results of several NSABP trials have shown that node-negative tumors do benefit from adjuvant 

treatment (Fisher et al., 2001). In 235 estrogen receptor-negative patients, the 8-year relapse-free survival rate (RFS) was 90% 

in those who received surgery and adjuvant chemotherapy, compared with 81% in those who received surgery alone. In 1,024 

estrogen receptor-positive patients, the 8-year RFS was 95% in those who received standard chemotherapy with tamoxifen, 

93% in those who received tamoxifen alone, and 86% in those who received no adjuvant treatment. In another analysis of 

1,009 women with tumors less than 1 centimeter in size, it was found that the combination of radiation and tamoxifen was 

more effective than either radiation or tamoxifen alone in reducing the ipsilateral recurrence rate following lumpectomy (Fisher 

et al., 2002).

Recently, new diagnostic tests, developed in part from NCI-supported tumor banks in the Cooperative Groups, are refining 

risk levels for patients with node-negative breast cancer. Women with node-negative breast cancer have an overall survival rate 

of approximately 70% following surgery alone. Adjuvant chemotherapy can improve the outcome for women destined to 

relapse. However, our inability to predict relapse has resulted in the overtreatment of a significant percentage of these women. 

NCI began the PACCT (Program for Assessment of Clinical Cancer Tests), which brought together experts from across 

the country to assist in the design of a trial to examine prognosis in node-negative tumors. As a result, the NCI-sponsored 

Cooperative Group, NSABP, in collaboration with an industrial partner (Genomic Health, Inc.), developed the Oncotype 

DXTM Breast Cancer Assay (Paik, 2003), which provides a recurrence score that correlates very well with 10-year disease-free 

survival. The PACCT Working Group endorsed the use of the Oncotype DXTM Assay in the trial they are proposing for 

women with node-negative tumors.

For patients with operable breast cancer, the order in which the various treatment modalities are administered has traditionally 

been definitive surgery followed by adjuvant chemotherapy (when applicable), followed by radiation (when applicable), and 

then tamoxifen (when applicable). In the past, preoperative or neoadjuvant therapy was reserved for patients with inoperable 

breast cancer to render their tumors operable. Recent NCI-sponsored research is defining the role of preoperative systemic 

therapies in patients with operable disease:

■ Preoperative chemotherapy has demonstrated advantages over traditional postoperative adjuvant treatment and provides 

an opportunity for accelerated drug development. The NSABP B-18 trial demonstrated equivalent outcomes when 

chemotherapy is given before or after surgical resection of the primary breast tumor (Fisher et al., 1997). However, women 

with large tumors who had the chemotherapy first were able to undergo breast-conserving surgery more often than their 

counterparts. In addition, in this trial, the attainment of a pathologic complete remission (PCR) after four cycles of 

preoperative chemotherapy was strongly predictive of improved outcome. Thus, PCR may serve as a surrogate endpoint, 

thereby greatly accelerating the evaluation of new drugs and treatment approaches. This concept is being confirmed by 

the ongoing NSABP B-27 trial, which has completed enrollment and has demonstrated a higher PCR rate when docetaxel 

(Taxotere®) is given after the combination of doxorubicin (Adriamycin®) and cyclophosphamide (Bear et al., 2003). Diseasefree and overall survival results from this trial are awaited to confirm that patients attaining PCR have the best outcome. In 

the interim, new trials are being designed by two Cooperative Groups to capitalize on this approach:

◆ The NCI-supported American College of Surgeons Oncology Group is testing whether preoperative hormonal therapy 

can produce benefits for postmenopausal women with hormone-sensitive tumors, similar to that seen with preoperative 

chemotherapy.

◆ The NSABP is evaluating new chemotherapy doublets following standard AC chemotherapy in a new preoperative clinical 

trial.
October 2004 NCI Breast Cancer Progress Report

7-14 Chapter 7: Treatment

The trials described above will obtain tumor tissue before and after treatment to assess the genetic profile of the tumor and 

any changes that occur with therapy. This research should lead to genetic tumor profiles that can predict response to specific 

chemo-hormonal therapies.

NCI-sponsored clinical trials have continued to refine the doses, administration frequency, and duration of treatments used in 

patients with operable breast cancer.

■ Improvements in radiation therapy may lead to increased utilization of breast-conserving surgery and an improved quality 

of life. Recent advances in radiation techniques have demonstrated that partial breast irradiation (PBI) given over 5 to 7 

days may yield outcomes that are equivalent to the standard 6 weeks of external beam irradiation, which is typically given 

over the course of 30 visits to a radiation oncology facility (Baglan et al., 2003; Arthur et al., 2003). Two NCI-sponsored 

Cooperative Groups, NSABP and RTOG, are collaborating on a definitive trial in 3,000 women comparing standard wholebreast irradiation to PBI.

■ The NCI-sponsored C9741 trial, performed by The Breast Cancer Intergroup of North America (TBCI), demonstrated 

that giving the same dose of chemotherapy drugs every 2 weeks instead of the standard every 3 weeks led to improved 

disease-free and overall survival of women with node-positive breast cancer (Citron et al., 2003). This novel study actually 

tested two concepts in one trial. The study used standard adjuvant chemotherapy drugs: doxorubin (A), cyclophosphamide 

(C), and paclitaxel (T). It compared the combination of AC followed by T (ACàT) to the sequential administration of A 

followed by T and then C (AàTàC) when given either every 2 weeks or every 3 weeks. There was no difference according 

to whether the drugs were given together or in sequence, but the every-2-week schedule improved both disease-free survival 

and overall survival at 36 months of median follow-up.

■ The ongoing TBCI S0221 trial is determining whether there is benefit to using an even more “dose-dense” regimen. In 

this trial, the now standard every-2-week ACàT regimen is being compared to daily and weekly administration schedules 

(Phase III Randomized Study of Four Schedules of Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Patients 

With Node-Positive or High-Risk Node-Negative Breast Cancer).

Studies in patients with advanced breast cancer have shown prolonged survival following administration of hormonal therapies 

that specifically aim to interfere with estrogen stimulation or other tumor growth factors. Recent NCI-sponsored research has 

been directed at determining whether the therapies that prolong survival in patients with advanced disease are able to decrease 

the rate of disease recurrence in patients with early breast cancer.

■ Aromatase inhibitors (AIs)—compounds that interfere with the synthesis of natural estrogen—were originally used as 

second-line hormonal therapy in postmenopausal women with estrogen receptor (ER)-positive metastatic breast cancer and 

later approved for first-line use, in lieu of tamoxifen, in the same patient group. Recent trials have shown that there is benefit 

to using AIs in adjuvant settings for women with ER-positive, early-stage disease. Ongoing and planned trials are addressing 

priorities regarding the optimal duration of AI treatment, whether AIs should replace tamoxifen or be used sequentially 

following completion of tamoxifen therapy, and whether one AI is superior to others with respect to efficacy and toxicity.

■ The MA.17 trial, led by the National Cancer Institute of Canada, enrolled over 5,000 women, the majority of whom came 

from NCI-sponsored U.S. Cooperative Groups (Goss et al., 2003). The trial tested whether disease-free survival is extended 

by the addition of an AI, letrozole, after 5 years of adjuvant treatment with tamoxifen. Patients who were disease-free after 

5 years of tamoxifen therapy were randomized to letrozole or placebo for 5 years. This study was stopped early because 

significant decrease in recurrence was observed compared with the placebo group. While letrozole seemed to result in a slight 

increase in osteoporosis, other side effects were generally mild and well tolerated. Further follow-up of long-term toxicity 

will be important.

■ TBCI is leading the current MA.27 trial that directly compares two AIs, anastrozole and exemestane, to compare the eventfree survival in postmenopausal women with receptor-positive breast cancer (Phase III Randomized Adjuvant Study of 

Exemestane Versus Anastrozole With or Without Celecoxib in Postmenopausal Women With Receptor-Positive Primary 

Breast Cancer). 
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-15

■ In September 1998, trastuzumab (Herceptin®) was approved by the FDA for treatment of metastatic breast cancer. After 

recognizing the effectiveness of Herceptin® in advanced breast cancer, NCI-supported Cooperative Groups moved quickly 

to launch two adjuvant trials—N9831 (Phase III Randomized Study of Doxorubicin Plus Cyclophosphamide Followed by 

Paclitaxel With or Without Trastuzumab [Herceptin] in Women With Her-2-Overexpressing Node-Positive or High-Risk 

Node-Negative Breast Cancer) and NSABP B-31 (Phase III Randomized Study of Doxorubicin and Cyclophosphamide 

Followed by Paclitaxel With or Without Trastuzumab [Herceptin] in Women With Node-Positive Breast Cancer That 

Overexpresses HER2)—to determine whether chemotherapy with Herceptin® is more effective than chemotherapy without 

Herceptin® in tumors that overexpress Her2/neu.

■ Bisphosphonates are agents that interfere with bone osteoclasts and are able to disrupt the development of bone metastases 

from breast tumors. The bisphosphonate pamidronate (Aredia®) is approved in the U.S. for the treatment of advanced 

metastatic disease. NSABP is performing a definitive trial to test whether the oral bisphosphonate, clodronate, would 

prevent the development of bone metastases in the adjuvant setting (Phase III Randomized Study of Adjuvant Clodronate 

With or Without Systemic Chemotherapy and/or Tamoxifen in Women With Early Stage Breast Cancer). In addition, 

TBCI and NSABP are collaborating on a trial to compare clodronate, zoledronate, and ibandronate to determine whether 

there is a preferable bisphosphonate for the prevention of breast cancer metastases.

Nonoperable Disease

Nonoperable breast cancer, encompassing Stage IIIB and metastatic Stage IV disease, is treated systemically with first-line 

chemotherapy and/or hormonal agents. Second-line and subsequent treatments are attempted when first-line treatments are 

ineffective or when progression occurs in patients who had previously shown full or partial responses.

Although metastatic breast cancer is considered incurable, considerable effort has been directed at identifying treatments that 

prolong survival while maintaining quality of life. Patients with progressing metastatic breast cancer are generally the first 

population in which novel approaches and agents are tested for efficacy. Some of the new treatments examined in recent NCIsponsored research include:

■ The angiogenesis inhibitor, bevacizumab (Avastin®), in combination with paclitaxel as first-line treatment (Phase III 

Randomized Study of Paclitaxel With or Without Bevacizumab in Patients With Locally Recurrent or Metastatic Breast 

Cancer)

■ The combination of fenretinide and tamoxifen (Phase III Randomized Study of Adjuvant Tamoxifen/Fenretinide Versus 

Tamoxifen/Placebo in Postmenopausal Women With Receptor-Positive Breast Cancer [Zujewski et al, 1999])

■ The retinoid alitretinoin in combination with tamoxifen (Lawrence et al., 2001)

■ The combination of all-trans retinoic acid and tamoxifen (Budd et al., 1998)

■ The cell-cycle kinase inhibitor flavoperidol (Tan and Swain, 2002)

■ R11557 (Zarnestra®), an inhibitor of protein farnesylation, in combination with the aromatase inhibitor letrozole (Zujewski 

et al, 2000)

■ ZD1839 (Iressa®), an epidermal growth factor inhibitor, in combination with Herceptin® (Phase II Study of Trastuzumab 

(Herceptin®) and Gefitinib in Patients With Metastatic Breast Cancer That Overexpresses Her2-neu).

■ Her2/neu vaccines (Disis et al., 2004)

■ Anti-MUC-1 monoclonal antibody (Phase I Study of Vaccination Comprising Recombinant Vaccinia-MUC-1 and 

Recombinant Vaccinia-TRICOM Vaccine in Patients With Metastatic Breast Cancer)

■ The apoptosis-inducing drug ceramide for treatment of cutaneous breast cancer (Phase II Study of Topical Ceramide Cream 

in Women With Cutaneous Breast Cancer).

■ Topotecan for advanced breast cancer (Levine et al., 1999)
October 2004 NCI Breast Cancer Progress Report

7-16 Chapter 7: Treatment

■ Paclitaxel and carboplatin as first-line chemotherapy (Perez et al., 2000).

■ The intracellular histamine antagonist N, N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE) and doxorubicin 

for patients with anthracycline-naïve metastatic breast cancer (Khoo et al., 1999).

Continuing Needs and Evolution

High priorities for breast cancer treatment research include the development of noninvasive approaches for primary breast 

cancer ablation and the development of targeted agents that are specific for the various molecular subtypes of breast cancer. 

Likewise, the discovery of nontoxic agents that block recently understood aspects of the estrogen receptor pathway is critical, as 

these agents can potentially be used with existing hormonal therapies to improve treatment response rates. Furthermore, efforts 

to understand patterns of drug sensitivity and resistance would be greatly facilitated by increasing the number of studies that 

systematically collect tissue samples before and after various therapies.

New areas for development in treatment-based imaging include image-guided applications to enhance intervention efficacy and 

integrating noninvasive imaging techniques to better appreciate the activity and mechanism of action of targeted therapies in 

Phase I and II studies. Additionally, newer clinical trial studies may include: (1) large, randomized studies that assign specific 

treatments based on new molecular parameters; (2) treatment studies in advanced disease based upon the early detection of 

micrometastases; and (3) smaller adjuvant trials that use pathologic complete response as a definitive endpoint (once this 

intermediate endpoint is established).

Progress in breast cancer treatment research would be enhanced by the establishment of standards of data collection that 

facilitate inter-Institute collaboration, data sharing, and leveraging of projects. The recently established cancer Biomedical 

Informatics Grid (caBIG) is a major development to facilitate these aims through standardization of computing tools, 

language, and resources for use by the cancer and biomedical research community. In a similar vein, enrollment in breast 

cancer treatment trials has been steadily improving over the past few years, ever since the establishment of the Cancer Trials 

Support Unit (CTSU). Breast cancer accounts for over 50% of all enrollments via this new NCI mechanism. The CTSU allows 

all qualified oncologists access to NCI-sponsored Phase III treatment trials, thereby speeding up the time to answer important 

questions and enhancing patient access to innovative therapies.

NCI-Supported Research Referenced in Chapter 7

Arthur DW, Vicini FA, Kuske RR, Wazer DE, Nag S. Accelerated partial breast irradiation: an updated report from the 

American Brachytherapy Society. Brachytherapy. 2003;2(2):124-130.

Baglan KL, Sharpe MB, Jaffray D, Frazier RC, Fayad J, Kestin LL, Remouchamps V, Martinez AA, Wong J, Vicini FA.

Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT). Int J Radiat Oncol Biol Phys. 2003 Feb 

1;55(2):302-311.

Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, 

Wolmark N; National Surgical Adjuvant Breast and Bowel Project Protocol B-27. The effect on tumor response of adding 

sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National 

Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-4174.

Budd GT, Adamson PC, Gupta M, Homayoun P, Sandstrom SK, Murphy RF, McLain D, Tuason L, Peereboom D, Bukowski 

RM, Ganapathi R. Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer. Clin Cancer 

Res. 1998 Mar;4(3):635-642.

Calvo A, Yokoyama Y, Smith LE, Ali I, Shih SC, Feldman AL, Libutti SK, Sundaram R, Green JE. Inhibition of the mammary 

carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. Int J Cancer. 2002 Sep 

20;101(3):224-234.
NCI Breast Cancer Progress Report October 2004

Chapter 7: Treatment 7-17

Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, 

Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L.

Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy 

as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and 

Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-1439.

Disis ML, Schiffman K, Guthrie K, Salazar LG, Knutson KL, Goodell V, dela Rosa C, Cheever MA. Effect of dose on immune 

response in patients vaccinated with an Her2/neu intracellular domain protein-based vaccine. J Clin Oncol. 2004 May 

15;22(10):1916-1925.

Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark 

N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women 

with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 

Jul;15(7):2483-2493.

Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, Margolese RG, Nesbitt L, Paik S, Pisansky TM, 

Wolmark N; National Surgical Adjuvant Breast and Bowel Project. Tamoxifen, radiation therapy, or both for prevention of 

ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin 

Oncol. 2002 Oct 15;20(20):4141-4149.

Fisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL, Wolmark N. Prognosis and treatment of patients with 

breast tumors of one centimeter or less and negative axillary lymph nodes. JNCI. 2001 Jan 17;93(2):112-120.

Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, Smith R, Begovic M, Dimitrov NV, Margolese 

RG, Kardinal CG, Kavanah MT, Fehrenbacher L, Oishi RH. Tamoxifen in treatment of intraductal breast cancer: National 

Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999 Jun 12;353(9169):1993-2000.

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston 

RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in 

postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):

1793-1802.

Green JE, Shibata MA, Shibata E, Moon RC, Anver MR, Kelloff G, Lubet R. 2-difluoromethylornithine and 

dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 

T/t-antigen transgenic mice. Cancer Res. 2001 Oct 15;61(20):7449-7455.

Khoo K, Brandes L, Reyno L, Arnold A, Dent S, Vandenberg T, Lebwohl D, Fisher B, Eisenhauer E. Phase II trial of N,Ndiethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl and doxorubicin chemotherapy in metastatic breast cancer: A National 

Cancer Institute of Canada clinical trials group study. J Clin Oncol. 1999 Nov;17(11):3431-3437.

Lawrence JA, Adamson PC, Caruso R, Chow C, Kleiner D, Murphy RF, Venzon DJ, Shovlin M, Noone M, Merino M, 

Cowan KH, Kaiser M, O’Shaughnessy J, Zujewski J. Phase I clinical trial of alitretinoin and tamoxifen in breast cancer 

patients: toxicity, pharmacokinetic, and biomarker evaluations. J Clin Oncol. 2001 May 15;19(10):2754-2763.

Levine EG, Cirrincione CT, Szatrowski TP, Canellos G, Norton L, Henderson IC. Phase II trial of topotecan in advanced 

breast cancer: a Cancer and Leukemia Group B study. Am J Clin Oncol. 1999 Jun;22(3):218-222.

Maroulakou IG, Anver M, Garrett L, Green JE. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat 

C3(1) simian virus 40 large tumor antigen fusion gene. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11236-11240.

Paik S. Clinical trial methods to discover and validate predictive markers for treatment response in cancer. Biotechnol Annu 

Rev. 2003;9:259-267. Review.

Perez EA, Hillman DW, Stella PJ, Krook JE, Hartmann LC, Fitch TR, Hatfield AK, Mailliard JA, Nair S, Kardinal CG, Ingle 

JN. A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. 

Cancer. 2000 Jan 1;88(1):124-131.
October 2004 NCI Breast Cancer Progress Report

7-18 Chapter 7: Treatment

Tan AR, Swain SM. Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer therapy. Semin Oncol. 2002 

Jun;29(3 Suppl 11):77-85. Review.

Wigginton JM, Park JW, Gruys ME, Young HA, Jorcyk CL, Back TC, Brunda MJ, Strieter RM, Ward J, Green JE, Wiltrout 

RH. Complete regression of established spontaneous mammary carcinoma and the therapeutic prevention of genetically 

programmed neoplastic transition by IL-12/pulse IL-2: induction of local T cell infiltration, Fas/Fas ligand gene expression, 

and mammary epithelial apoptosis. J Immunol. 2001 Jan 15;166(2):1156-1168.

Wu K, Kim HT, Rodriquez JL, Munoz-Medellin D, Mohsin SK, Hilsenbeck SG, Lamph WW, Gottardis MM, Shirley MA, 

Kuhn JG, Green JE, Brown PH. 9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigentransgenic mice. Clin Cancer Res. 2000 Sep;6(9):3696-3704.

Zujewski J, Horak ID, Bol CJ, Woestenborghs R, Bowden C, End DW, Piotrovsky VK, Chiao J, Belly RT, Todd A, Kopp 

WC, Kohler DR, Chow C, Noone M, Hakim FT, Larkin G, Gress RE, Nussenblatt RB, Kremer AB, Cowan KH. Phase I and 

pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol. 2000 Feb;18(4):

927-941.

Zujewski J, Pai L, Wakefield L, Giusti R, Dorr FA, Flanders C, Caruso R, Kaiser M, Goodman L, Merino M, Gossard M, 

Noone MA, Denicoff A, Venzon D, Cowan KH, O’Shaughnessy JA. Tamoxifen and fenretinide in women with metastatic 

breast cancer. Breast Cancer Res Treat. 1999 Oct;57(3):277-283.
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-1

Chapter 8:

Breast Cancer Control, Survivorship, and Outcomes: NCI’s Investment and Recent Progress

To reduce the burden of breast cancer, we must sustain a vigorous and substantial commitment to basic 

and applied cancer control research conducted by scientists from diverse disciplines. Such an integrated 

research effort should address monitoring, prevention, surveillance, detection, treatment, and followup, including the provision of compassionate palliative care to those who die of the disease.... A fuller 

understanding is needed as to which groups of women are at risk for poor quality of life and psychosocial 

outcomes, and at what points along the disease or care continuum risks are elevated. Charting the 

Course: Priorities for Breast Cancer Research

The ultimate goal of cancer control research, as defined by the 1998 Breast Cancer PRG report, is to eliminate the burden of 

cancer. NCI has made much progress toward this goal, and recent research has shown that early detection and treatment of 

breast cancer have contributed to reduced mortality. NCI is supporting research to increase the numbers of women screened, 

enhance screening methodologies, ensure that all women receive needed treatment, and maximize quality of life for the 

growing numbers of breast cancer survivors. Several Centers of Excellence are developing communication strategies that will 

inform women about behaviors that can reduce their risk of developing breast cancer, recruit more women for breast cancer 

screening, enhance women’s decision making about screening and treatment, and improve quality of life following breast 

cancer treatment. The seven research sites of the Breast Cancer Surveillance Consortium (BCSC) are assessing the accuracy, 

cost, quality, and intermediate outcomes of screening as it is practiced in the community. Data from the Consortium are 

critical to related NCI efforts (such as the Cancer Intervention and Surveillance Modeling Network [CISNET]) to estimate the 

impact of these practices on changes in breast cancer mortality. NCI-supported researchers are also addressing quality of life in 

breast cancer survivors and the impact of breast cancer on family members.

The PRG report identified 8 priorities that deal with important topics in breast cancer control research and 16 priorities 

that address critical issues in outcomes research. The cancer control priorities address the need to identify the mechanisms 

responsible for basic behavioral change, determine whether psychosocial factors influence traditional disease outcomes, 

facilitate better patient decision making, improve the delivery of breast cancer care to maximize desirable outcomes and 

minimize cost, identify the psychosocial benefits from unproven treatments, use advances in communications technology 

to study ways of delivering breast cancer information, determine the impact of breast cancer on the family, and identify 

communications strategies to reach diverse health providers. Outcomes priorities focus on the need to study the short- and 

long-term outcomes of multimodal treatment for breast cancer, investigate patient-focused outcomes across the continuum 

of age and for women with in situ breast cancer, integrate patient-focused data with biological prognostic information to 

make treatment decisions, improve patient outcomes, help meet survivors’ needs, identify resources to study patient-focused 

outcomes, improve the management of symptoms and side effects, incorporate patient preferences into treatment decisions, 

collect patient outcome data in prevention trials, and advance the field of outcomes research.

The NCI has been responsive to the PRG priorities related to breast cancer control, survivorship, and outcomes. Recent 

research has demonstrated that certain recruitment strategies can increase the numbers of women who are screened for breast 

cancer at recommended intervals. Several factors have been identified that can improve the accuracy of mammography. As 

a result of research, treatment following an abnormal mammogram has improved in recent years, and disparities in the care 

received are being addressed. As more women survive with breast cancer, researchers are identifying the factors—such as social 

support and exercise—that maximize physical and emotional functioning.

Since the release of the PRG report, NCI has sponsored or cosponsored at least four major reports that are relevant to the 

Cancer Control, Survivorship, and Outcomes recommendations of the Breast Cancer PRG. In addition, the National Institutes 
October 2004 NCI Breast Cancer Progress Report

8-2 Chapter 8: Control, Survivorship, and Outcomes

of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, November 1-3, 2000, addressed 

issues related to patient-focused outcomes when making decisions about adjuvant therapy (see Chapter 7 for details).

The first of these reports, Evaluating Screening Performance in Practice,

1

 was developed by the Breast Cancer Surveillance 

Consortium. The BCSC is a consortium of seven research sites and one statistical coordinating center established by the NCI 

to address issues that can be adequately examined only in a very large sample drawn from diverse geographic and practice 

settings. This report describes the BCSC’s current areas of research and its accomplishments to date, including more than 130 

papers in peer-reviewed journals. One of the studies highlighted in the BCSC report found that screening mammography 

was less effective for detecting cancer in younger women than in older women, regardless of family history. This study shows 

the importance of further research to determine whether screening mammography is accurate enough to support screening 

recommendations for younger women with a family history of breast cancer. Another study found that mammography was 

equally accurate in black and white women but that black women with symptoms had larger and more aggressive tumors than 

white women. These results indicate that more research is needed to clarify the relationship between race/ethnicity, modifiable 

risk factors, and stage of disease at diagnosis.

The second report, Exploring the Role of Cancer Centers for Integrating Aging and Cancer Research,

2

 summarizes the deliberations 

of a workshop organized by the NCI and the National Institute on Aging. The report notes the disproportionately high burden 

of cancer for older Americans, a particular concern in the context of the aging population in the United States. Workshop 

participants met in seven breakout sessions focused on such issues as treatment efficacy and tolerance; effects of comorbidity 

and cancer; and psychological, social, and medical issues. Each group developed three recommendations, including: 

incorporate the clinical expertise from NCI projects, particularly the NCI SEER projects, that is available in cancer centers to 

improve the quality of care of the medically underserved, aging population; develop clinical trials that are specifically designed 

for older cancer patients; develop models for decision making at the individual and clinical levels; and examine the cancer 

caregivers’ functioning and quality of life and their impact on the older cancer patient’s care and treatment trajectory. This 

report resulted in an NCI Program Announcement: Integrating Aging and Cancer Research.

The NCI’s 2002 Report of the Breast Screening Working Group, prepared at the request of the NCI Director, was developed in 

response to debates in the professional literature and the news media about mammography’s efficacy in certain age groups. 

This internal report was intended to help the Institute improve how it translates complex research evidence for the public and 

to examine the state of the science and what research and resources are needed to promote progress in breast cancer screening 

and diagnosis. The Working Group made several recommendations in its report, including increasing basic research on interval 

cancers, tumor microenvironment, and ductal carcinoma in situ (DCIS), and supporting translational research, technology 

development, and interdisciplinary collaboration. The Working Group also recommended that NCI communicate proactively 

and clearly about research on screening mammography to ensure that its key audiences are well informed.

The NCI cosponsored the Institute of Medicine’s report Meeting Psychosocial Needs of Women With Breast Cancer.

3

 This 

report was intended to examine the psychological consequences of the cancer experience, the availability and application 

of psychosocial services for women with cancer, and the training and education of cancer care providers. In a review of the 

literature, the report concludes that psychosocial interventions can be expected to reduce psychiatric symptoms and improve 

quality of life in routine breast cancer care. The report presents recommendations for providers and the delivery of care 

through: (1) promoting formal psycho-oncology education for oncology providers; (2) integrating standards of psychosocial 

care with cancer managemen; and (3) conducting collaborative studies to enhance the integrated coordination of care. The 

report also recommends to continue studies on psycho-oncology research and to encourage an NCI special study to ascertain 

the use of, and current need for, cancer-related supportive care services in the United States, including disparities by age, race/

ethnicity, geography, and insurance coverage.

1 This report can be found on the BCSC Web site at http://breastscreening.cancer.gov/espp.pdf. 

2 Available at http://www.nia.nih.gov/health/nianci/.

3 A brief review of this report can be found on the IOM Web site at http://www.iom.edu/report.asp?id=18136.
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-3

NCI’s Investment and Response

From FY1998 to 2003, NCI’s extramural investment in breast cancer control, survivorship, and outcomes research increased 

from $46.6 million to $82.8 million (Figure 8-1). This increase in funding corresponds to increases in the number of projects 

that are responsive to the 24 Breast Cancer PRG research priorities for cancer control, survivorship, and outcomes.

NCI’s research support is summarized in Table 8-1 for the 8 Breast Cancer PRG research priorities pertaining to cancer control 

and in Table 8-2 for the 16 research priorities pertaining to outcomes.4

Table 8-1. NCI Efforts Responsive to PRG Priorities and Opportunities in Cancer Control Researcha

PRG Priority:

What are the mechanisms responsible for basic 

behavioral change? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included compliance with 

mammography screening guidelines, with 

an emphasis on older women, African 

Americans, and Hispanics; the relationship between trust and breast cancer prevention practices and behaviors in 

African Americans; the long-term physiological, psychological, social, and religious/spiritual effects of surviving cancer 

on older adults; and the impact of concerns about mortality on behavioral risk factors for cancer.

■ On October 14-16, 1998, NCI sponsored the 5 A Day International Symposium to address the health benefits of 

increased fruit and vegetable intake and behavior change interventions in community settings.

■ NCI initiatives addressing this priority included the Small Grants Program for Behavioral Research in Cancer Control 

and Social and Cultural Dimensions of Health. 

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Fiscal Year

Millions of Dollars

4 A project may map to more than one PRG priority and, therefore, be represented in more than one figure. Projects active in 2003 are listed in Appendix B (Tables B-40 to 

B-58) by Principal Investigator’s name for each PRG priority.

a. Some of the original PRG priorities are addressed jointly in Table 8-1 because these priorities address partially overlapping issues and they are relevant to many of 

the same research projects and initiatives.

0

5

10

15

20

25

1998 1999 2000 2001 2002 2003

Year

Projects

Figure 8-1. NCI’s extramural investment in cancer control, survivorship, 

and outcomes research in breast cancer: 1998-2003 (in millions of dollars)
October 2004 NCI Breast Cancer Progress Report

8-4 Chapter 8: Control, Survivorship, and Outcomes

PRG Priority:

Do psychosocial factors including, but not limited 

to, interventions influence traditional disease 

outcomes (e.g., overall survival, disease-free survival, 

and disease response)?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the motivations to obtain 

follow-up care of women who had experienced a false-negative mammogram; the relationships between breast cancer 

treatments and disease-specific and health-related quality of life outcomes; and the impact of environmental toxins, 

diet, physical activity, and weight gain on breast cancer risk.

■ NCI initiatives addressing this priority included the Breast Cancer Specialized Programs of Research Excellence 

(SPOREs); Economic Studies in Cancer Prevention, Screening and Care; and Integrating Aging and Cancer Research.

PRG Priorities:

How can we facilitate better patient decision 

making, especially that based on risks and 

benefits? (Control-C)

How can patient-focused data be integrated 

with biological prognostic information 

to make the best treatment decisions? 

(Outcomes-D)

How can patient preferences be incorporated 

into treatment decisions? (Outcomes-L)

Discussion and resolution of social and 

legal issues of informed consent and 

privacy of medical information in the 

context of genetic testing and genetic 

predisposition.b (Genetics-F)

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation relevant to the following 

priorities included:

◆ Control-C: comparative cancer 

epidemiology, prevention, and control 

in older minority populations; barriers 

to the use of symptom-management strategies by patients; the impact of culture, ethnicity, and income on screening 

behaviors; and the effects of education and counseling on the emotional, physical, and social adjustment of breast 

cancer patients

b. This priority was part of the Genetics section in the original Breast Cancer PRG report.

0

10

20

30

40

50

60

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

0

2

4

6

8

10

1998 1999 2000 2001 2002 2003

Year

Outcomes-D Outcomes-L Genetics-F

0

5

10

15

20

25

1998 1999 2000 2001 2002 2003

Year
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-5

◆ Outcomes-D: a new functional evaluation tool for assessing cancer care, psychological and immune parameters 

associated with fatigue in breast cancer survivors, and performance status for decisions about therapies and eligibility 

for clinical trials

◆ Outcomes-L: breast cancer patients’ preferences for local and systemic therapy

◆ Genetics-F: decisions about chemoprevention by families with hereditary breast and ovarian cancer and genetic 

counseling for these families

■ Examples of clinical trials addressing these priorities included the following:

◆ Randomized Genetics Study of Educational Methods for Patients With Breast or Ovarian Cancer Enrolling in a 

Breast Cancer Genetics Program (NCI-99-C-0081)

◆ Chemotherapy Decisions and Outcomes in Older Women With Newly Diagnosed Breast Cancer (CALGB-369901)

◆ Companion Study to Evaluate Quality of Life in Women With Axillary Node-Negative, Estrogen ReceptorNegative, Primary Invasive Breast Cancer Enrolled on Protocol NSABP-B-23 (NSABP-B-23-QOL)

■ NCI initiatives addressing these priorities included the Cancer Centers Program, Insight Awards to Stamp Out Breast 

Cancer, and Special Populations Networks.

PRG Priority:

Can the delivery of breast cancer care from 

diagnosis and screening through treatment, 

follow-up, and end of life be improved in 

ways that maximize desirable outcomes and 

minimize cost?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included culturally sensitive 

educational materials to improve screening 

use in minority populations; the impact 

of changes in behaviors, clinical practice 

patterns of health care providers, and interventions on incidence and mortality; effects and costs of a prevention case 

manager to improve cancer early detection; and a comparison of cancer diagnoses, interventions, and clinical and cost 

outcomes between persons with and without disabilities.

■ Examples of clinical trials addressing this priority included the following:

◆ Correlation of Menstrual Cycle Phase at the Time of Surgery With Disease-Free Survival in Premenopausal Women 

With Stage I or II Breast Cancer (NCCTG-N9431)

◆ Randomized Study of Brief Physician-Initiated Smoking Cessation Strategies Versus Usual Care in Patients With 

Early-Stage Cancer Who Are Undergoing Treatment in Clinical Oncology Settings (NCI-P93-0042)

■ NCI initiatives addressing this priority included Aging Women and Breast Cancer, Minority Institution/Cancer 

Center Partnership (MI/CCP), and Small Grants Program for Behavioral Research in Cancer Control.

0

20

40

60

80

100

120

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

8-6 Chapter 8: Control, Survivorship, and Outcomes

PRG Priority:

What psychosocial benefits do patients obtain from 

unproven treatments that cause them to seek out 

such treatments? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included spiritually based health 

education in African-American women and 

treating chemotherapy-induced nausea with 

acupressure.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase III Randomized Study of Acupressure for Chemotherapy-Induced Nausea in Women With Breast Cancer 

Receiving One of Three Combination Therapy Regimens (MDA-NUR01-396)

◆ Phase III Randomized Study of Black Cohosh for the Management of Hot Flashes in Women With Breast Cancer 

or Who Have Concerns About Developing Breast Cancer (NCCTG-N01CC)

◆ Randomized Study of Acupuncture for Mucositis-Related Pain Secondary to High-Dose Chemotherapy in Patients 

Undergoing Hematopoietic Stem Cell Transplantation (NCI-03-C-0125)

◆ Phase I/II Randomized Study of Adjuvant Doxorubicin and Cyclophosphamide With or Without Chinese Herbal 

Therapy for Symptom Management in Women With Stage I, II, or Early Stage III Breast Cancer 

(UCSF-CRO-97755)

◆ Study of the Use of Complementary and Alternative Medicine Practices by Women at Increased Risk for Breast 

Cancer (NCI-00-C-0039)

■ On June 9-11, 2000; October 19-21, 2001; and April 9-13, 2003, NCI sponsored Comprehensive Cancer Care: 

Integrating Complementary and Alternative Therapies to provide information on complementary and alternative 

therapies (CAM) for cancer to oncologists, other practitioners, and people with cancer.

■ NCI initiatives addressing this priority included Basic and Preclinical Research on Complementary and Alternative 

Medicine (CAM) and Centers for Complementary and Alternative Medicine Research.

PRG Priority:

How can advances in communication 

technologies best be used for research in health 

communications and behavior change and for 

delivering breast cancer information? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included: methods to improve 

recruitment of patients, especially from 

minority and low-income populations, into 

community-based clinical oncology trials; tailored and culturally appropriate communications interventions to 

increase mammography use; cancer communication among minority populations, including African Americans; and 

education about risk factors and methods for risk reduction.

0

5

10

15

20

25

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

0

1

2

3

4

1998 1999 2000 2001 2002 2003

Year

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-7

■ On October 25-28, 2000, NCI sponsored the 11th Annual Conference of the Cancer Patient Education Network 

(CPEN): Caring, Discovery, Excellence to exchange information among patient educators from each of the NCIdesignated Comprehensive and Clinical Cancer Centers.

■ NCI initiatives addressing this priority included the Cancer Centers Program, Centers of Excellence in Cancer 

Communication Research, and Health Communications in Cancer Control.

PRG Priority:

What is the impact of breast cancer on the family? 

Specifically, what is its impact on other family 

members and the family unit, and what is the impact 

of the family unit on breast cancer outcomes? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included the impact of psychosocial 

factors on cancer screening behaviors among 

unmarried women, the effect of education and 

counseling on patients with breast cancer and their partners, and helping mothers with breast cancer support their 

children.

■ NCI initiatives addressing this priority included the Cancer Outcomes Measurement Working Group (COMWG), 

Research on the Impact of Cancer on the Family, and Small Grants Program for Behavioral Research in Cancer 

Control.

PRG Priority:

What kind of communication strategies are needed to 

reach the diversity of health care providers in the area 

of breast cancer? 

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included patterns and outcomes of screening 

mammography practice in North Carolina and 

increasing the participation of minority scientists in 

behavioral and translational cancer research.

■ NCI initiatives addressing this priority included Cancer Research Training, Career Development, and Education 

Opportunities; the MI/CCP; and Special 

Populations Networks (SPNs).

Additional Breast Cancer Control Projects

NCI Efforts:

■ Active research projects in FY2003 related 

to reducing breast cancer health disparities 

included: studies of risk-related behaviors and 

changes in diet and lifestyle in Hispanic breast 

0

2

4

6

8

10

12

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

0

10

20

30

40

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects

0

2

4

6

8

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

8-8 Chapter 8: Control, Survivorship, and Outcomes

cancer survivors; use of mammograms and/or clinical breast exams and trust in health care providers among black 

women by level of education, age, income, and Hispanic ethnicity; physician and patient predictors of tamoxifen 

prescription and treatment adherence in older women; and impact of culture on cancer screening in Chinese women.

■ The PRG did not address screening in the context of cancer control, but several areas of investigation on this topic 

were active in FY2003, including the impact of community factors (such as availability of medical providers) on 

screening for breast cancer; how low-income African-American women interpret and act on health education messages 

regarding mammography; effects of soy on estrogen levels and mammographic densities; and the effects of driving 

distance on mammography use.

■ In FY2003, other examples of active areas of investigation included the association between the incidence of breast 

cancer and body size at different ages, diabetes, and dietary patterns related to insulin resistance and post-treatment 

behavioral risk factors for recurrence of secondary breast tumors or new primaries.

■ Examples of clinical trials addressing screening in the context of cancer control included the following:

◆ Screening and Diagnostic Study of Magnetic Resonance Imaging in Women With Suspected Breast Cancer 

(UPCC-ACR-6884)

◆ Randomized Screening and Diagnostic Study of Digital Mammography Versus Screen-Film Mammography in the 

Detection of Breast Cancer in Women (ACRIN-6652)

Table 8-2. NCI Efforts Responsive to PRG Priorities and Opportunities in Outcomes Researcha

PRG Priority:

How can patient-focused outcomes be studied 

across the continuum of age? The impact of breast 

cancer treatments may be different among different 

age groups.

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included reproductive cancer 

education resources for women with breast 

cancer, educating older women about managing uncertainty after breast cancer treatment, helping the mother with 

breast cancer support her child, and facilitating positive adaptation to a breast cancer diagnosis.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase II Randomized Study of Soy Protein in Postmenopausal Women With Breast Disease Taking Tamoxifen and 

Experiencing Hot Flashes (CALGB-79805)

◆ Phase III Study of the Effect of Menstrual Cycle Timing With Breast Surgery on Prognosis in Premenopausal 

Women With Stage I, II, or III Breast Cancer (UCLA-9810046)

◆ Phase III Randomized Study of Risedronate for Prevention of Bone Loss in Premenopausal Women Undergoing 

Chemotherapy for Primary Breast Cancer (NCCTG-N02C1)

a. Some of the original PRG priorities are addressed jointly in Table 8-2 because these priorities address partially overlapping issues and they are relevant to many of 

the same research projects and initiatives.

0

5

10

15

20

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-9

■ On October 19-20, 2000, NCI sponsored Cancer Survivorship Throughout the Lifespan: Challenges for the 21st Century

to address the complex medical, psychological, and social needs of cancer survivors.

■ NCI initiatives addressing this priority included Integrating Aging and Cancer Research, SEER-Medicare Linked 

Database, and Small Grants Program for Cancer Epidemiology.

PRG Priority:

What are the patient-focused outcomes for women 

with in situ breast cancer? 

NCI Efforts:

■ In FY2003, examples of active areas of investigation 

included assessing quality of life for women with 

DCIS and studying the effects of various treatment 

regimens on quality of life for DCIS patients.

■ Examples of clinical trials addressing this priority 

included the following:

◆ Screening Study Following Local Excision in Selected Patients With Ductal Carcinoma In Situ (DCIS) of the Breast 

(E-5194)

◆ Phase III Randomized Study of Hormone Replacement Therapy for Hot Flashes and/or Vaginal Symptoms in 

Postmenopausal Women With a History of Node-Negative Invasive Carcinoma or Ductal Carcinoma In Situ of the 

Breast Who Are Receiving Adjuvant Tamoxifen (E-2193)

PRG Priorities:

What are the short- and long-term effects 

of multimodal treatment for breast cancer? 

(Outcomes-A)

How can we improve patient outcomes, 

including the physical, emotional, and social 

dimensions of health-related quality of life? 

(Outcomes-E)

How can the management of disease symptoms 

and treatment side effects be improved? 

(Outcomes-H)

How can the long-term medical and 

psychosocial outcomes for breast cancer 

survivors be improved? (Outcomes-I)

NCI Efforts:

■ In FY2003, examples of active areas of investigation relevant to the following priorities included:

◆ Outcomes-A: investigating the cognitive deficits experienced by breast cancer patients undergoing systemic 

chemotherapy versus surgery plus radiotherapy, assessing the impact of breast cancer recurrence on Vietnamese 

women following various multimodal treatment regimens, and testing the effect of a breast tumor vaccine plus 

chemotherapy on tumor-specific immunity.

0

2

4

6

8

1998 1999 2000 2001 2002 2003

Year

NC0I-Supported Projects

2

4

6

8

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

0

20

40

60

80

100

120

140

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

Outcomes-A Outcomes-E

Outcomes-H Outcomes-I
October 2004 NCI Breast Cancer Progress Report

8-10 Chapter 8: Control, Survivorship, and Outcomes

◆ Outcomes-E: assessing quality of life among minority cancer survivors, interactive cancer communication systems to 

improve the quality of life of patients and families facing cancer across the disease spectrum, insomnia intervention 

strategies for breast cancer patients, and using exercise to fight fatigue in breast cancer patients.

◆ Outcomes-H: the influence of sleep/wake rhythms on patients’ tolerance of treatment and quality of life, changes in 

brain structure and function associated with chemotherapy, healthy weight management strategies for breast cancer 

survivors, and information for breast cancer survivors on issues that present or persist post treatment.

◆ Outcomes-I: assessing cognitive effects of chemotherapy treatment in women with breast cancer, the relationship 

between low-fat diet and breast cancer recurrence, a follow-up study to measure breast cancer survivor’s healthrelated quality of life, and determining the physiologic, psychologic, and social long-term effects of surviving cancer 

on older adults.

■ Examples of clinical trials addressing these priorities included the following:

◆ Randomized Study of Health Promotion in Patients Who Are Prostate or Breast Cancer Survivors 

(DUMC-1547-02-8R4ER)

◆ Phase III Randomized Study of Palliative Radiation Therapy for Bone Metastases From Breast or Prostate Cancer 

(RTOG-9714)

◆ Oral Analgesia Regimen for Improved Pain Control in Cancer Patients (E-4Z93)

◆ Phase II Study of High-Dose Chemotherapy, Total Body Irradiation, and Autologous Peripheral Blood or Bone 

Marrow Transplantation in Patients With Hematologic Malignancies or Selected Chemosensitive Solid Tumors 

(RPCI-DS-9115)

◆ On October 19-20, 2000, NCI sponsored Cancer Survivorship Throughout the Lifespan: Challenges for the 21st 

Century to address the complex medical, psychological, and social needs of cancer survivors. A second conference, on 

June 2-4, 2002, addressed Cancer Survivorship: Resilience Across the Lifespan.

◆ A report entitled Meeting the Psychosocial Needs of Women With Breast Cancer, cosponsored by the NCI, Centers for 

Disease Control and Prevention, and National Academy of Sciences, was released by the Institute of Medicine in 

January 2004

■ NCI initiatives addressing this priority included Cancer Intervention and Surveillance Modeling Network (CISNET), 

Cancer Outcomes Measurement Working Group (COMWG), Minority and Underserved Cancer Survivors, Small Grants 

Program for Behavioral Research in Cancer Control, and Social and Cultural Dimensions of Health.

PRG Priority:

How are the health care needs of breast cancer 

survivors being met within the current health 

care system? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included telephone therapies 

that help women cope with breast cancer, 

assesment of the quality of care provided 

to Medicare patients with breast cancer, and evaluation of the determinants of quality of care for older breast cancer 

survivors.

■ Examples of clinical trials addressing this priority included the following:

0

2

4

6

8

10

12

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-11

◆ Randomized Study of Health Promotion in Patients Who Are Prostate or Breast Cancer Survivors 

(DUMC-1547-02-8R4ER)

◆ Randomized Study of the Effect of Telephone Counseling by Breast Cancer Survivors on Well-Being of Women 

With Recurrent Breast Cancer (SWOG-S9832)

■ On October 19-20, 2000, NCI sponsored Cancer Survivorship Throughout the Lifespan: Challenges for the 21st Century

to address the complex medical, psychological, and social needs of cancer survivors. A second conference, on June 2-4, 

2002, addressed Cancer Survivorship: Resilience Across the Lifespan.

■ NCI initiatives addressing this priority included Minority and Underserved Cancer Survivors, SEER Patterns of Care/

Quality of Care (POC/QOC) Initiative, and Social and Cultural Dimensions of Health.

PRG Priorities:

What treatment research resources exist to foster 

research on patient-focused outcomes? (Outcomes-G)

What kinds of prevention research resources exist 

to facilitate patient-focused outcomes research? 

(Outcomes-N)

What cancer control and survivorship research resources 

are available to advance the field of outcomes research? 

(Outcomes-P)

NCI Efforts:

■ In FY2003, examples of active areas of investigation relevant to the following priorities included:

◆ Outcomes-G: a new functional evaluation tool for cancer care, a cancer chemotherapy program project, and studies 

to test the effect of adjuvant therapy on long-term survival

◆ Outcomes-N: a computerized decision-support tool that educates women about their breast cancer risk factors 

and risk reduction strategies and numerous Community Clinical Oncology Programs that participate in the Breast 

Cancer Prevention Trial

◆ Outcomes-P: use of HMO data to characterize patterns of care and analyze the relationship between treatment 

and outcomes for breast cancers, as well as partnerships between NCI-designated Cancer Centers and minority 

institutions to assess breast cancer outcomes in underserved communities

■ NCI initiatives addressing this priority included the CISNET, COMWG, Cancer Surveillance Using Health ClaimsBased Data System, Community Clinical 

Oncology Program (CCOP), and 

Minority-Based CCOP (MBCCOP).

PRG Priority:

What secondary prevention and health 

promotion efforts are effective and 

appropriate for breast cancer patients/

survivors?

0

10

20

30

40

50

60

70

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects

Outcomes-G Outcomes-N Outcomes-P

0

20

40

60

80

100

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

8-12 Chapter 8: Control, Survivorship, and Outcomes

NCI Efforts:

■ In FY2003, examples of active areas of investigation included assessing the impact of several dietary factors—including 

isothiocyanates and d-limonene, vegetables and vegetable juice, and limited fat—on risk of breast cancer recurrence, 

design of effective interventions for preventing osteoporosis in breast cancer survivors, and the effects of exercise and 

healthy weight management on quality of life and morbidity in survivors of breast cancer.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase I Study of Perillyl Alcohol in Women at Risk for Recurrent Breast Cancer (CCF-IRB-3574)

◆ Phase II Study of Pentostatin in Patients With Refractory Chronic Graft-Versus-Host Disease (CALGB-100101)

◆ Randomized Study of Raloxifene With or Without Exercise Versus Exercise Alone in Women Previously Treated for 

Breast Cancer (OHSU-6312)

◆ Randomized Study of Health Promotion in Patients Who Are Prostate or Breast Cancer Survivors 

(DUMC-1547-02-8R4ER)

■ On October 19-20, 2000, NCI sponsored Cancer Survivorship Throughout the Lifespan: Challenges for the 21st Century

to address the complex medical, psychological, and social needs of cancer survivors. A second conference, on June 2-4, 

2002, addressed Cancer Survivorship: Resilience Across the Lifespan.

■ NCI initiatives addressing this priority included the Small Grants Program for Behavioral Research in Cancer Control 

and Minority and Underserved Cancer Survivors.

PRG Priority:

What are the economic and health care outcomes 

for patients/survivors with breast cancer?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included assessing the effectiveness 

and cost-effectiveness of alendronate on 

bone mineral density and bone turnover in 

premenopausal women treated with adjuvant 

chemotherapy for breast cancer; determining the effects of various treatment strategies on DCIS recurrence rates, 

survival, costs, and quality of life; and labor market outcomes of long-term breast cancer survivors.

■ NCI initiatives addressing this priority included COMWG; Cancer Research Network (CRN); Cancer Surveillance 

Using Health Claims-Based Data System; and Economic Studies in Cancer Prevention, Screening, and Care.

PRG Priority:

What patient outcomes data are being collected in 

prevention trials?

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included clinical research in cancer 

treatment and cancer control/prevention through 

0

2

4

6

8

10

12

1998 1999 2000 2001 2002 2003

Year

Projects

0

20

40

60

80

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-13

participation in NCI-supported trials and increasing the availability of protocol-based cancer prevention and control 

research trials to urban and rural minorities.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase I Study of Indole-3-Carbinol for the Prevention of Breast Cancer in Nonsmoking Women at High Risk for 

Breast Cancer (KUMC-8508-01)

◆ Phase II Trial of Dietary Fatty Acids: Roles in Hormonally Mediated Cancers in Normal Premenopausal Women 

(UMN-9509M10234)

◆ Pilot Chemoprevention Study of Tamoxifen and Fenretinide in Subjects at High Risk for Developing Invasive Breast 

Cancer (NCI-94-C-0056L)

■ NCI initiatives addressing this priority included the Clinical Trials Cooperative Groups Program and the CCOP.

PRG Priority:

How can patient-focused outcomes for women 

with advanced metastatic breast cancer be 

improved? 

NCI Efforts:

■ In FY2003, examples of active areas of 

investigation included improving pain 

management in women with breast cancer, 

assessing symptom occurrence and severity 

in low-income and racially disparate groups 

of patients with metastatic breast cancer, and 

improving palliative care for patients with breast cancer.

■ Examples of clinical trials addressing this priority included the following:

◆ Phase I Study of Recombinant Vaccinia DF3/MUC1 Vaccine in Patients With Metastatic Breast Cancer 

(DFCI-97050)

◆ Phase II Pilot Study of High Dose Doxorubicin, Cyclophosphamide, Paclitaxel, and Amifostine Followed by 

Peripheral Stem Cell Rescue in Patients With High-Risk Stage II/III and Responsive Stage IV Advanced Breast 

Cancer (CHNMC-IRB-99002)

◆ Phase II Study of High-Dose Chemotherapy With Autologous Peripheral Blood Progenitor Cell Rescue for Women 

With Metastatic Breast Cancer, Plus Evaluation of Outpatient Imipenem for Neutropenic Fever (MSKCC-94077)

◆ Phase III Randomized Comparison of High Dose Chemotherapy Plus Filgrastim to Filgrastim for Mobilization of 

Peripheral Blood Stem Cells for Autologous Transplantation for Patients With Responsive Metastatic Breast Cancer 

or High-Risk Stage II and III Patients (MDA-DM-95047).

■ NCI initiatives addressing this priority included the Breast SPOREs

0

1

2

3

4

5

6

1998 1999 2000 2001 2002 2003

Year

NCI-Supported Projects
October 2004 NCI Breast Cancer Progress Report

8-14 Chapter 8: Control, Survivorship, and Outcomes

Additional Breast Cancer Outcomes 

Projects

NCI Efforts:

■ Active research projects in FY2003 related 

to reducing breast cancer health disparities 

included psychological adjustment among 

rural breast cancer survivors, quality of life in 

African-American and Hispanic survivors of 

breast cancer, and determinants of the quality 

of care of older breast cancer survivors.

■ In FY2003, examples of other active areas of investigation included the relationship between postmenopausal hormone 

therapy and breast cancer mortality, the risk of developing endometrial cancer and breast cancer as a result of exposure 

to tamoxifen, enhancing the well-being of individuals recently diagnosed with breast cancer through increased verbal 

processing of traumatic events, and a computer-based imaging system to reduce anxiety and distress relating to 

alopecia in women being treated for breast cancer.

The initiatives relevant to research on breast cancer control, survivorship, and outcomes between FY1998 and 2003 include 

the following list of general initiatives that are described in Table 2-15 (Chapter 2) and the category-specific initiatives that are 

listed and described in Table 8-3.6

■ Aging Women and Breast Cancer

■ Basic and Preclinical Research on Complementary and Alternative Medicine

■ Breast and Ovarian Cancer Family Registries (CFRs)

■ Breast Cancer Surveillance Consortium (BCSC)

■ Cancer Biomedical Informatics Grid (caBIG)

■ Cancer Centers Program

■ Cancer Genetics Services Directory

■ Cancer Research Network

■ Cancer Research Training, Career Development, and Education Opportunities 

■ Clinical Trials Cooperative Group Program 

■ Community Clinical Oncology Program (CCOP)

■ Developmental/Pilot Projects in Cancer Complementary and Alternative Medicine (CAM)

■ Exploratory Grants for Correlative Laboratory Studies and Clinical Trials

■ Insight Awards to Stamp Out Breast Cancer

■ Integrating Aging and Cancer Research

■ International Breast Cancer Screening Network

5 Initiatives that impact multiple categories of breast cancer research.

6 Initiatives that are unique to the cancer control, survivorship, and outcomes research category.

0

2

4

6

8

10

12

1998 1999 2000 2001 2002 2003

Year

NCI-Supported

Projects
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-15

■ Minority-Based Community Clinical Oncology Program (MBCCOP)

■ Minority Institution/Cancer Center Partnership (MI/CCP) 

■ NCI Center for Bioinformatics (NCICB) 

■ Small Grants Program for Cancer Epidemiology

■ Southern Community Cohort Study (SCCS)

■ Special Population Networks

■ Specialized Programs of Research Excellence (SPOREs) in Breast Cancer

Table 8-3. NCI Initiatives Relevant to Breast Cancer Research: Cancer Control, Survivorship, and Outcomesa

Initiatives With Breast Cancer-Relevant Components

■ Basic Biobehavioral Research on Cancer-Related Behaviors (RFA-CA-99-014)

◆ Overview: Supports research on the links among biology, behavior, and the environment as they pertain to cancerrelated risk behaviors.

◆ Relevant Research Projects Resulting From This RFA: Between 1998 and 2003, one project relevant to breast cancer 

research was supported through this RFA. This project can be found in Appendix B, Table B55, by searching for the 

RFA number.

■ Cancer Control PLANET (http://cancercontrolplanet.cancer.gov/)

◆ Overview: A collaborative effort aimed at providing access to data and resources that can help cancer control 

planners, health educators, program staff, and researchers design, implement, and evaluate evidence-based 

cancer control programs. It is now being expanded to include tools for primary care clinicians that facilitate the 

implementation of proven cancer control techniques in practice. Cancer Control PLANET is jointly supported by 

NCI, the Centers for Disease Control and Prevention (CDC), the American Cancer Society (ACS), the Substance 

Abuse and Mental Health Services Administration, and the Agency for Healthcare Research and Quality.

◆ Relevant Resource Resulting From This Initiative: The Web portal provides access to resources that can assist in:

Assessing the cancer and/or risk factor burden within a given state

Identifying potential partner organizations that may already be working with high-risk populations

Understanding the current research findings and recommendations

Accessing and downloading evidence-based programs and products

Finding guidelines for planning and evaluation

■ Cancer Intervention and Surveillance Modeling Network (CISNET) (http://cisnet.cancer.gov/about)

◆ Overview: A consortium of NCI-sponsored researchers whose focus is to use modeling techniques to describe the 

impact of prevention, screening, and/or treatment interventions in population-based settings.

a Lists of the projects derived from each initiative can be located on the online Supplement to the Breast Cancer Progress Report: Initiative Database.
October 2004 NCI Breast Cancer Progress Report

8-16 Chapter 8: Control, Survivorship, and Outcomes

◆ Relevant Projects Resulting From This Initiative: There are currently seven funded projects within the consortium 

that focus on breast cancer:

Breast Cancer Trend Analysis Using Stochastic Simulation

Breast Cancer: Role of Early Detection, Treatment, and Prevention

Cancer Intervention and Surveillance Modeling Network (CISNET)

Mechanistic Modeling of Breast Cancer Surveillance

Outcomes Across the Spectrum of Breast Cancer Care

Simulating Breast Cancer in Wisconsin

Surveillance of Breast Cancer Trends by MISCAN

Specific projects can be found in Appendix B, Tables B7, B9, B31, B41, B43, B51, B52, and B58, by searching for 

the RFA number (CA99-013).

■ Cancer Outcomes Measurement Working Group (COMWG) (http://outcomes.cancer.gov/methods/measures/

comwg)

◆ Overview: Members of COMWG evaluate existing endpoint measures, including health-related quality of life, 

economic burden, and patient satisfaction. They also work to formulate alternative strategies for identifying valid, 

reliable, sensitive, and feasible clinical and patient-centered endpoint measures for use in quality of cancer care 

studies. Thirty-five members of the working group were selected to provide expertise in outcomes measurement for 

four cancer sites, including breast cancer.

◆ Relevant Resource Resulting From This Initiative: Findings of the Working Group have been reported to the NCI 

and will be published as the book Outcomes Assessment in Cancer.

■ Cancer Surveillance Using Health Claims-Based Data System (http://dccps.nci.nih.gov/ARP/research/health.asp)

◆ Overview: Support for research to investigate the utility of health claims information as a reporting source for 

assessing the national cancer burden.

◆ Relevant Projects Resulting From This Initiative: Between 1998 and 2003, five projects relevant to breast cancer 

research were supported through this initiative. Specific projects can be found in Appendix B, Tables B49, B52, and 

B53, by searching for the PA number (PA-99-015).

■ Cancer Survivorship Studies in Established Epidemiologic Cohorts (PA-98-027)

◆ Overview: Fosters research on issues related to long-term cancer survivorship through the use of existing 

epidemiologic study populations, particularly in the areas of specific health or lifestyle outcomes and their 

modulation by common risk factors and other exposures.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, three projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B2, B29, and B30, 

by searching for the PA number.

■ Centers for Complementary and Alternative Medicine Research (RFA-AT-00-001)

◆ Overview: Research conducted at these centers will examine the potential efficacy, safety, and validity of 

complementary and alternative medicine practices, as well as the physiological or psychological mechanisms 

underlying or contributing to the effects of these practices.
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-17

◆ Relevant Resources Resulting From This Initiative: The National Center for Complementary and Alternative 

Medicine (NCCAM) Web site provides information on complementary and alternative medicine practices, 

advisories, treatment options, clinical trials, and funding information. Seven NCCAM clinical trials are applicable to 

breast cancer:

Acupuncture for Shortness of Breath in Cancer Patients

Distance Healing in Wound Healing after Breast Reconstruction Surgery

Macrobiotic Diet and Flax Seed: Effects on Estrogens, Phytoestrogens, & Fibrinolytic Factors

Massage Therapy for Breast Cancer Treatment-Related Swelling of the Arms and Legs

Massage Therapy for Cancer-Related Fatigue

Mistletoe Extract and Gemcitabine for the Treatment of Solid Tumor Cancers

Pycnogenol for the Treatment of Lymphedema of the Arm in Breast Cancer Survivors

■ Centers of Excellence in Cancer Communication Research (http://dccps.nci.nih.gov/eocc/ceccrs_index.html)

◆ Overview: Supports research and outreach aimed at increasing knowledge of, access to, and use of cancer 

communication tools by the public, patients, survivors, and health professionals. These Centers provide essential 

infrastructure to facilitate rapid advances in knowledge about cancer communications, translate theory and programs 

into practice, and train health communication scientists.

◆ Projects Resulting From This Initiative: Four academic institutions were established as Centers of Excellence in 

Cancer Communication Research in 2003. The following Centers are actively pursuing breast cancer-relevant 

projects:

Saint Louis University: Capture on videotape the stories of 80 African-American breast cancer survivors, examine 

the effectiveness of these stories in promoting mammography in 900 African-American women, and test a new 

explanatory model of narrative cancer communication effects

University of Michigan: A multiphased experimental process to explore methods of communicating risk regarding 

tamoxifen prophylaxis to women at high risk for breast cancer

University of Wisconsin, Madison: Controlled trial will examine whether breast cancer patient outcomes change 

as different types of conceptually distinct CHESS (Comprehensive Health Enhancement Support System) services 

(information, social support, and skills training) are systematically added to a patient’s treatment resources

■ Digital Divide Pilot Projects (http://cancercontrol.cancer.gov/eocc/ddpp_awards.html)

◆ Overview: Supports research and programs to understand and eventually breach the Digital Divide that exists 

among many minority populations in accessing and utilizing cancer information on the Internet.

◆ Relevant Projects Resulting From This Initiative: In collaboration with NCI’s North Central and Mid-West Regions 

Cancer Information Service (CIS), the University of Wisconsin and the Karmanos Cancer Center will expand 

the CHESS Program that puts personal computers and Web-based support resources into the homes of AfricanAmerican breast cancer patients.

■ Economic Studies in Cancer Prevention, Screening and Care 

(http://cancercontrol.cancer.gov/ARP/research/economic.asp)

◆ Overview: Supports research directed toward increasing knowledge of the economic aspects of cancer prevention, 

screening, and care.
October 2004 NCI Breast Cancer Progress Report

8-18 Chapter 8: Control, Survivorship, and Outcomes

◆ Relevant Projects Resulting From This Initiative:

Long-Term Cost and Outcomes of Breast Cancer Screening

Tamoxifen & Breast Cancer—Acceptance/Cost Effectiveness

Use of Cancer Screening in a Managed Care Environment

■ Exploratory Grants for Behavioral Research in Cancer Control (PA-99-163)

◆ Overview: Supports the development of novel or conceptually creative ideas that may produce innovative advances 

in the behavioral sciences, specifically in the areas of cancer prevention and control.

◆ Relevant Research Projects Resulting From This PA: Between 1998 and 2003, 12 projects relevant to breast cancer 

research were supported through this PA. Specific projects can be found in Appendix B, Tables B45, B51, and B53-

55, by searching for the PA number.

■ Health Communications in Cancer Control (RFA-CA-98-014)

◆ Overview: Supports research on the use of interactive digital media in cancer prevention and control and promotes 

the refinement of communications systems to improve dissemination of cancer control-related information.

◆ Relevant Research Projects Resulting From This RFA: Between 1998 and 2003, three projects relevant to breast 

cancer research were supported through this RFA. Specific projects can be found in Appendix B, Table B51, by 

searching for the RFA number.

■ Long-Term Cancer Survivors: Research Initiatives (RFA-CA-04-003)

◆ Overview: Promotes and supports research that will lead to the decrease in physiologic and psychosocial morbidity 

and mortality associated with long-term (over 5 years) survival from cancer.

◆ Relevant Research Projects Resulting From This RFA: Between 1998 and 2003, three projects relevant to breast 

cancer research were supported through this RFA. Specific projects can be found in Appendix B, Tables B40, B49, 

and B51, by searching for the RFA number and the previously issued number (RFA-CA-97-018).

■ Minority and Underserved Cancer Survivors (http://cancercontrol.cancer.gov/ocs/underserved)

◆ Overview: Supports supplements to NCI-designated Cancer Centers for research on cancer survivorship among 

minority and underserved cancer populations in community settings.

◆ Relevant Projects Resulting From This Initiative:

Breast Cancer Survivors & Community Support

Follow-Up Care in Breast Cancer Survivors

Reproductive Health in African-American Breast Cancer Survivors

■ Research on the Impact of Cancer on the Family (http://dccps.nci.nih.gov/bb/research_family.html)

◆ Overview: Supports supplemental awards to NCI-funded Clinical and Comprehensive Cancer Centers to expand 

the study of the impact of cancer on the family.

◆ Relevant Projects Resulting From This Initiative: Studies at ten institutions were funded that spanned the life cycle, 

focusing on both child and adult caregivers, and addressed multiple cancer sites, including breast, colon, prostate, 

brain, head and neck, and pediatric cancers.
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-19

■ Research Supplements for Underrepresented Minorities (http://cancercontrol.cancer.gov/ocs/underrepresented/)

◆ Overview: Supplements research support to: (1) reach out to minority graduate and undergraduate students 

studying biomedical or behavioral sciences; and (2) provide an opportunity to develop research capabilities.

◆ Relevant Projects Resulting From This Initiative: Five projects are supported through this program, most of which 

are generally applicable to behavioral, survivorship, and communication research. The following project is directly 

related to breast cancer research:

Young Breast Cancer Survivors: A Population-Based Cohort

■ SEER-Medicare Linked Database (http://healthservices.cancer.gov/seermedicare)

◆ Overview: Supports a large database that incorporates two large population-based sources of data that provide 

detailed information about elderly persons with cancer. The data come from the Surveillance, Epidemiology, and 

End Results (SEER) program of cancer registries that collect clinical, demographic, and cause-of-death information 

for persons with cancer and the Medicare claims for covered health care services from the time of a person’s Medicare 

eligibility until death.

◆ Relevant Resource Resulting From This Initiative: The SEER-Medicare Linked Database Web site includes a section 

on analytic support to assist researchers who use the database.

■ SEER Patterns of Care/Quality of Care (POC/QOC) Initiative (http://cancercontrol.cancer.gov/bb/seer_pattern.html)

◆ Overview: Evaluates the dissemination of state-of-the-art therapy into community practice, disseminates findings 

in scientific journals and professional meetings, and works with professional organizations to develop relevant 

educational or training opportunities.

◆ The SEER registries perform POC/QOC studies every 3 to 5 years for the major cancer sites (including breast). 

Cancer sites with emerging new treatments or concerns regarding provision of state-of-the-art therapy would be 

conducted in alternate years.

■ Small Grants Program for Behavioral Research in Cancer Control (http://dccps.nci.nih.gov/smallgrants/index.html)

◆ Overview: Designed to encourage investigators from a variety of academic, scientific, and public health disciplines to 

apply their skills to behavioral research investigations in cancer prevention and control.

◆ Relevant Research Projects Resulting From This Initiative: Between 1998 and 2003, 30 projects relevant to breast 

cancer research were supported through this initiative. Specific projects can be found in Appendix B, Tables B9, 

B10, B12, B33, B41, B43, B47, and B51, by searching for the PA numbers (PAR-02-037 and PAR-99-006).

■ Social and Cultural Dimensions of Health (PA-02-043)

◆ Overview: Encourages further development of health-related social sciences.

◆ Relevant Projects Resulting From This PA: Pending—this PA will remain open until December 21, 2004.

■ Surveillance, Epidemiology and End Results (SEER) (http://seer.cancer.gov)

◆ Overview: Database of information on cancer incidence and mortality. SEER currently collects and publishes 

data from 11 population-based cancer registries and 3 supplemental registries. Approximately 26% of the 

U.S. population is represented, including a substantial portion of racial/ethnic minorities and other medically 

underserved individuals.

◆ Relevant Resource Resulting From This Initiative: SEER recently published the Annual Report to the Nation on the 

Status of Cancer, 1975-2000, which updates statistics on four main cancer types, including breast.
October 2004 NCI Breast Cancer Progress Report

8-20 Chapter 8: Control, Survivorship, and Outcomes

■ Translating Research into Improved Outcomes (TRIO) (http://cancercontrol.cancer.gov/bb/trio.html)

◆ Overview: Supports efforts to move research discoveries through program development into evidence-based 

service delivery. Three overarching goals include: (1) closing the discovery-delivery gap by disseminating cancer 

and behavioral surveillance data to identify needs, track progress, and motivate national, state, and local action; 

(2) collaborating with public health, clinical practice, and voluntary organizations to reduce the overall cancer 

burden and eliminate cancer health disparities; and (3) working with national, regional, state, and local partner 

organizations to identify and overcome the infrastructure barriers to the adoption of evidence-based cancer control 

programs and practices.

◆ Relevant Resource Resulting From This Initiative: TRIO supports communication efforts in breast cancer screening 

through the breast cancer screening section of the Cancer Control PLANET Web portal and the NCI/USDA/ACS/

CDC collaboration in eight states promoting breast and cervical cancer screening among women never or rarely 

screened who live in high-mortality counties.

Ongoing NCI Research: Recent Progress in Breast Cancer 

Control, Survivorship, and Outcomes

The Importance of Mammography

Early detection of breast cancer through periodic examinations and mammography is considered the most effective method 

of breast cancer control. Although breast cancer screening methods have advanced substantially in the last few years, these 

are only of benefit to women who are actually screened. Recent research has shown that women are more likely to obtain 

a mammogram if they receive tailored communications. Specifically, women who receive targeted educational materials or 

telephone counseling are up to 20% more likely than women receiving standard care to obtain a mammogram within the 

recommended period (Champion et al., 2003; Clark and Wold, 2002; McCaul and Wold, et al., 2002). Although telephone 

and mailed reminders have both been tested, the most effective methods to encourage screening are combined interventions 

in which women receive written communications as well as motivational telephone interviews or in-person counseling with a 

letter from a physician (Champion et al., 2003; Valanis et al., 2003; Legler et al., 2002).

Advances in education have helped increase the use of mammography; in 1998, almost 70% of U.S. women age 40 or older 

reported receiving a mammogram within the last 2 years, compared with less than 30% of women in 1987 (Legler et al., 2002; 

Swan et al., 2003). As a result, mammography was the only type of cancer screening test for which the Healthy People 20007

goal was reached. Unfortunately, not all populations have experienced these dramatic improvements, as older individuals, those 

with less education, and those with lower incomes are still less likely to be screened than other women (Hiatt et al., 2002; 

Meissner et al., 2003). In addition, while differences in mammography rates have narrowed between Caucasian and AfricanAmerican women in recent years, rates for Hispanic women remain lower than those of either group (Legler et al., 2002). This 

issue remains important for our nation because, among women with late-stage cancer, over 50% have not undergone screening 

(Taplin et al., 2004 in press). To approach the mortality reduction goals for the year 2010, we must screen women of all 

backgrounds and reach those who have not been screened.

Factors Affecting the Accuracy of Mammography

Although screening mammography is the best technique available for reducing mortality from breast cancer, mammography 

does not detect every breast cancer. Much has been learned in recent years about some of the factors that affect the ability of 

mammography to accurately detect cancer. We now know, for example, that in a population offered screening, 40% of latestage cancers occur among women who have had negative screening tests within the previous 3 years (Taplin et al., 2004).

7 Healthy People 2000 is available at http://odphp.osophs.dhhs.gov/pubs/hp2000.
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-21

One key factor is breast density, which makes the interpretation of mammograms challenging because dense breast tissue can 

resemble cancerous tissue on mammographic film (Carney et al., 2003; Mandelson et al., 2000; Rosenberg et al., 1998). Breast 

density appears to be associated with several factors, including age, race, and hormone usage. Breast density decreases with age, 

so it is perhaps not surprising that the accuracy of mammography increases with age (Barlow et al., 2002; Carney et al., 2003; 

Rosenberg et al., 1998; Ziv et al., 2003). Asian and black women are more likely than white women to have dense breasts, 

although black and white women over 65 have similar breast density (El-Bastawissi et al., 2001). However, researchers found 

that screening mammography is as accurate in black women as in white women after controlling for age, breast density, and 

time since the previous mammogram (Gill and Yankaskas, 2004). Women who use hormone replacement therapy (HRT) are 

two to three times as likely as women who do not use HRT to have dense breasts, but these differences decrease when HRT 

use is stopped (Rosenberg et al., 1998; Rutter et al., 2001). The impact of HRT on mammography accuracy appears to be 

completely attributable to the fact that HRT use increases breast density (Carney et al., 2003).

Another factor that influences the quality of the screening process is breast positioning during the mammogram procedure. 

Specifically, mammograms are up to 20% more likely to detect cancers when the breast is positioned properly on the machine, 

and women with cancers found after a negative mammogram result are more than twice as likely to have been positioned 

improperly at the time of the screening examination (Taplin et al., 2002).

Quality of Care

Although a vast literature addresses the use of screening mammography for breast cancer, less attention has been devoted to 

follow-up of abnormal test results. Recent research has begun to address this gap, showing that over 25% of patients with 

an abnormal screening mammography result do not receive the recommended follow-up care. Thus, barriers to appropriate 

follow-up exist at the provider, patient, and health care system levels (Yabroff et al., 2003). Rates of inappropriate follow-up are 

even higher in some populations, as almost one-third of black women with an abnormal mammogram or clinical breast exam 

do not receive appropriate follow-up 6 months after being screened (Kerner et al., 2003).

Treatment provided to women with early-stage breast cancer appears to be consistent with the results of national consensus 

conferences and clinical trials addressing this topic (Guadagnoli et al., 1998; Harlan et al., 2002); however, some disparities 

remain in the care of women with breast cancer. For example, women of low socioeconomic status are more likely than others 

to be diagnosed with late-stage cancer, to experience a recurrence, and to die from breast cancer (Bradley, Given, et al., 2002; 

Gordon, 2003). In addition, elderly women enrolled in an HMO are less likely to have breast cancer diagnosed at a late stage 

and more likely to receive breast-conserving therapy than women enrolled in a fee-for-service setting (Riley et al., 1999). 

However, other disparities have decreased. Specifically, investigators have shown that African-American women tend to be 

diagnosed with breast cancer at the same stage, receive the same treatment, and have the same survival rates as white women 

after controlling for several patient characteristics, such as age, disease stage, socioeconomic status, and insurance coverage 

(Bradley, Given, et al., 2002; Gordon, 2003). Furthermore, disabled women have the same risk of dying from breast cancer as 

women who are not disabled (Roetzheim and Chirikos, 2002).

Survivors’ Issues

Women with a history of breast cancer account for over 40% of all female cancer survivors. As the number of breast cancer 

survivors increases, it is becoming increasingly apparent that these women are much more resilient than previously assumed.

Breast cancer survivors report a broad range of physical symptoms after completing treatment (Michael et al., 2000). Some 

groups of women are at greater risk for adverse effects following breast cancer diagnosis and treatment; women who have had 

adjuvant chemotherapy and those who are younger appear to be more likely than other women to experience problems with 

general health, physical functioning, and social functioning (Ganz et al., 2002).

Behavioral research has demonstrated that social support mediates individuals’ general well-being, and this may be particularly 

true after a cancer diagnosis. An analysis of data from the Nurses’ Health Study found that level of social integration is an 

important predictor of subsequent health-related outcomes for breast cancer survivors—even more than treatment or tumor 

characteristics. On average, socially isolated women were more adversely affected by breast cancer than socially integrated 
October 2004 NCI Breast Cancer Progress Report

8-22 Chapter 8: Control, Survivorship, and Outcomes

women in terms of their role function, vitality (feeling energetic and alert), and physical function. Rehabilitation programs 

should emphasize interventions that address the availability of adequate social support (Michael et al., 2002).

It now appears that the threat to life imposed by cancer can be life altering, especially with respect to health behaviors. In 

one study examining this effect, researchers found that after their cancer diagnosis, almost half of smokers quit smoking, and 

a similar proportion of study participants improved their dietary habits; however, one-third exercised less (Blanchard et al., 

2003). Several researchers are studying the risk for physical inactivity following cancer and its corresponding adverse impact on 

weight and health; these researchers are using exercise interventions to improve survivors’ emotional and functional well-being. 

The results for breast cancer survivors are compelling: exercise training programs have beneficial effects on cardiopulmonary 

function and quality of life (Courneya, Mackey, et al., 2003; Pinto et al., 2003), reduce fatigue, and help maintain functional 

ability (Kolden et al., 2002), and, when combined with group psychotherapy, may improve women’s quality of life beyond 

the benefits of group therapy alone, especially with respect to physical and functional outcomes (Courneya, Friedenreich, et 

al., 2003). While it is not clear if these types of interventions will alter the course of cancer (i.e., rate of or time to recurrence 

or death), such programs hold promise for reducing cancer-related morbidity and promoting general health. They also appear 

to have enormous appeal to survivors eager to reduce the perceived stress in their lives and take control of their bodies after 

cancer.

As the number of long-term survivors increases, the indirect morbidity and disability costs of breast cancer may also be rising. 

Research indicates that breast cancer has an economic impact on long-term survivors. In one study, survivors who were 

working when they were originally diagnosed experienced much larger reductions in their annual earnings over 5 years than 

working control subjects (Chirikos et al., 2002). Breast cancer survivors are also 10% less likely to be working than women 

without breast cancer. However, women who survive breast cancer and continue to work report working approximately 3 more 

hours a week than women who do not have cancer. This suggests that the morbidity associated with certain types and stages of 

breast cancer and its treatment does not interfere with a woman’s ability to work (Bradley, Bednarek, et al., 2002).

Continuing Needs and Evolution

In spite of recent progress, most women in the United States still do not obtain recommended annual mammograms. 

Advances are clearly needed in communications strategies to educate more women about the importance of mammography. 

More research is also needed on barriers to screening and ways to reduce them to ensure that all women are screened at 

recommended intervals. Furthermore, mechanisms need to be identified to reduce health disparities by increasing the rate at 

which underserved populations receive mammography screening. Disparities in treatment, including likelihood of receiving 

breast-conserving surgery and outcomes of various breast cancer treatments, also require further exploration. In addition, we 

need new screening techniques that are more sensitive and specific than mammography and that offer improved data storage, 

transmission of results, cost, and ease of use. Because the accuracy of individual radiologists in interpreting mammograms 

varies (depending on such factors as training, experience, and type of screening program), more research is needed on sources 

of variation and ways to increase radiologists’ accuracy.

NCI-Supported Research Referenced in Chapter 8

Barlow WE, Lehman CD, Zheng Y, Ballard-Barbash R, Yankaskas BC, Cutter GR, Carney PA, Geller BM, Rosenberg R, 

Kerlikowske K, Weaver DL, Taplin SH. Performance of diagnostic mammography for women with signs or symptoms of breast 

cancer. JNCI. 2002 Aug 7;94(15):1151-1159.

Blanchard CM, Denniston MM, Baker F, Ainsworth SR, Courneya KS, Hann DM, Gesme DH, Reding D, Flynn T, Kennedy 

JS. Do adults change their lifestyle behaviors after a cancer diagnosis? Am J Health Behav. 2003 May-Jun;27(3):246-256.

Bradley CJ, Bednarek HL, Neumark D. Breast cancer and women’s labor supply. Health Serv Res. 2002;37:1309-1328.

Bradley CJ, Given CW, Roberts C. Race, socioeconomic status, and breast cancer treatment and survival. JNCI. 2002 Apr 

3;94(7):490-496.
NCI Breast Cancer Progress Report October 2004

Chapter 8: Control, Survivorship, and Outcomes 8-23

Carney PA, Miglioretti DL, Yankaskas BC, Kerlikowske K, Rosenberg R, Rutter CM, Geller BM, Abraham LA, Taplin SH, 

Dignan M, Cutter G, Ballard-Barbash R. Individual and combined effects of age, breast density, and hormone replacement 

therapy use on the accuracy of screening mammography. Ann Intern Med. 2003 Feb 4;138(3):168-175.

Champion V, Maraj M, Hui S, Perkins AJ, Tierney W, Menon U, Skinner CS. Comparison of tailored interventions to increase 

mammography screening in nonadherent older women. Prev Med. 2003 Feb;36(2):150-158.

Chirikos TN, Russell-Jacobs A, Cantor AB. Indirect economic effects of long-term breast cancer survival. Cancer Pract. 2002 

Sep-Oct;10(5):248-255.

Clark MA, Rakowski W, Ehrich B, Rimer BK, Velicer WF, Dube CE, Pearlman DN, Peterson KK, Goldstein M. The effect of 

a stage-matched and tailored intervention on repeat mammography. Am J Prev Med. 2002;22(1):1-7.

Courneya KS, Friedenreich CM, Sela RA, Quinney HA, Rhodes RE, Handman M. The group psychotherapy and home-based 

physical exercise (group-hope) trial in cancer survivors: physical fitness and quality of life outcomes. Psychooncology. 2003 

Jun;12(4):357-374.

Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in 

postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol. 2003 May 1;21(9):1660-

1668.

El-Bastawissi AY, White E, Mandelson MT, Taplin S. Variation in mammographic breast density by race. Ann Epidemiol. 2001 

May;11(4):257-263.

Ganz PA, Desmond KA, Leedham B, Rowland JH, Meyerowitz BE, Belin TR. Quality of life in long-term, disease-free 

survivors of breast cancer: a follow-up study. JNCI. 2002 Jan 2;94(1):39-49.

Gill KS, Yankaskas BC. Screening mammography performance and cancer detection among black women and white women in 

community practice. Cancer. 2004 Jan 1;100(1):139-148.

Gordon NH. Socioeconomic factors and breast cancer in black and white Americans. Cancer Metastasis Rev. 2003 Mar;22(1):

55-65.

Guadagnoli E, Weeks JC, Shapiro CL, Gurwitz JH, Borbas C, Soumerai SB. Use of breast-conserving surgery for treatment of 

stage I and stage II breast cancer. J Clin Oncol. 1998 Jan;16(1):101-106.

Harlan LC, Abrams J, Warren JL, Clegg L, Stevens J, Ballard-Barbash R. Adjuvant therapy for breast cancer: practice patterns 

of community physicians. J Clin Oncol. 2002 Apr 1;20(7):1809-1817.

Hiatt RA, Klabunde C, Breen N, Swan J, Ballard-Barbash R. Cancer screening practices from National Health Interview 

Surveys: past, present, and future, A review. JNCI. 2002 Dec 18;94:1837-1846.

Kerner JF, Yedidia M, Padgett D, Muth B, Washington KS, Tefft M, Yabroff KR, Makariou E, Freeman H, Mandelblatt JS. 

Realizing the promise of breast cancer screening: Clinical follow-up after an abnormal screening results among black women. 

Prev Med. 2003; 37:92-101.

Kolden GG, Strauman TJ, Ward A, Kuta J, Woods TE, Schneider KL, Heerey E, Sanborn L, Burt C, Millbrandt L, Kalin NH, 

Stewart JA, Mullen B. A pilot study of group exercise training (GET) for women with primary breast cancer: feasibility and 

health benefits. Psychooncology. 2002 Sep-Oct;11(5):447-456.

Legler J, Meissner HI, Coyne C, Breen N, Chollette V, Rimer BK. The effectiveness of interventions to promote 

mammography among women with historically lower rates of screening. Cancer Epidemiol Biomarkers Prev. 2002 Jan;11(1):

59-71.

Mandelson MT, Oestreicher N, Porter PL, White D, Finder CA, Taplin SH, White E. Breast density as a predictor of 

mammographic detection: comparison of interval- and screen-detected cancers. JNCI. 2000 Jul 5;92(13):1081-1087.
October 2004 NCI Breast Cancer Progress Report

8-24 Chapter 8: Control, Survivorship, and Outcomes

McCaul KD, Wold KS. The effects of mailed reminders and tailored messages on mammography screening. J Community 

Health. 2002 Jun;27(3):181-190.

Meissner HI, Breen N, Yabroff KR. Whatever happened to clinical breast examinations? Am J Prev Med. 2003;25(3):259-263.

Michael YL, Berkman LF, Colditz GA, Holmes MD, Kawachi I. Social networks and health-related quality of life in breast 

cancer survivors: a prospective study. J Psychom Res. 2002 May;52(5):285-293.

Michael YL, Kawachi I, Berkman LF, Holmes MD, Colditz GA. The persistent impact of breast carcinoma on functional 

health status: prospective evidence from the Nurses’ Health Study. Cancer. 2000 Dec1;89(11):2176-2186.

Pinto BM, Clark MM, Maruyama NC, Feder SI. Psychological and fitness changes associated with exercise participation 

among women with breast cancer. Psychooncology. 2003 Mar;12(2):118-126.

Riley GF, Potosky AL, Klabunde C, Warren JL, Ballard-Barbash R. Breast cancer stage at diagnosis and treatment patterns 

among older women in HMOs and fee-for-service. JAMA. 1999;281:720-726.

Roetzheim RG, Chirikos TN. Breast cancer detection and outcomes in a disability beneficiary population. J Health Care Poor 

Underserved. 2002 Nov;13(4):461-476.

Rosenberg RD, Hunt WC, Williamson MR, Gilliland FD, Wiest PW, Kelsey CA, Key CR, Linver MN. Effects of age, breast 

density, ethnicity, and estrogen replacement therapy on screening mammographic sensitivity and cancer stage at diagnosis: 

review of 183,134 screening mammograms in Albuquerque, New Mexico. Radiology. 1998 Nov;209(2):511-518.

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