When I look into the eyes of a patient 

losing the battle with cancer, I say to 

myself, “It doesn’t have to be this way.” 

— Andrew C. von Eschenbach, M.D. 

Director, National Cancer Institute, 

physician, cancer survivor 

When I look into the eyes of a patient 

losing the battle with cancer, I say to 

myself, “It doesn’t have to be this way.” 

—	 Andrew C. von Eschenbach, M.D. 

Director, National Cancer Institute, 

physician, cancer survivor 

The Nation’s Investment in 

Cancer Research 

A Plan and Budget Proposal 

for Fiscal Year 2004 

Prepared by the Director 

National Cancer Institute 

NATIONAL INSTITUTES OF HEALTH 

U.S. Department of Health 

and Human Services 
. . . working to achieve a future when all cancers are 

The National Cancer Institute 

controlled or eliminated. 

Through studies of the cell, we: 

■ Explore how specific cancer-causing mutations and protein 

errors disrupt normal cellular communication and lead to 

uncontrolled growth and loss of normal function. 

■ Learn which genes and proteins play a key role in cancer 

invasion and spread. 

■ Develop molecular agents that will interact with 

malfunctioning proteins to prevent cancerous growth. 

With studies of cancer in the context of the person, we: 

■ Identify the integral ways that surrounding cells and 

tissues contribute to tumor growth — and the means of 

manipulating this microenvironment to defeat the cancer. 

■ Apply new technologies and informatics to detect cancer 

and monitor therapy. 

■ Learn how to prevent and treat cancer with agents and 

technologies that attack the cancer, but leave the person 

unharmed. 

With population studies, we: 

■ Investigate gene-environment interactions that increase 

people’s risk of developing cancer and their need for 

enhancing prevention and early detection measures. 

■ Identify specific ways to reduce cancer risk by changing 

behavior and eliminating harmful environmental exposures. 

■ Develop effective communication and delivery strategies to 

ensure that all people benefit from cancer prevention, 

early detection, and treatment.


“Without research, there is no hope.” 

— The Honorable Paul G. Rogers, 

Sponsor, National Cancer Act of 1971 

Front cover graphic: Scanning electron micrograph of metastatic lung cancer cells in culture, 

courtesy of Jeffrey Wyckoff, Jeffrey E. Segall, and John Condeelis at the Albert Einstein 

College of Medicine and the Analytical Imaging Facility at the Albert Einstein College of Medicine, 

an Albert Einstein Comprehensive Cancer Center shared resource. 
Director’s Message 

We as a nation stand at that defining moment in history when a surge of new technologies and 

the fruits of many years of investigation will yield, over the next two decades, unimagined leaps forward 

in our understanding of cancer and our ability to control and eliminate it. To take full advantage of these 

opportunities, three themes will dominate NCI’s planning and decision making: discovery, development, 

and delivery. Our challenge will be to continue to accelerate the engine of discovery; to translate 

knowledge gained about the genetic, molecular, and cellular basis of cancer into the development of 

interventions to detect, diagnose, treat, and prevent cancer; and to ensure that these interventions are 

delivered to all who need them. 

We need to hone our efforts toward an integrated 

systems approach to the study of cancer. We must take 

advantage of the explosion in technology and biological research to comprehensively weave together 

the disparate pieces of knowledge that reveal how 

cancer develops and progresses within the context 

of the human system. That is, we must consider 

the protein along with the gene that produces it, 

the tumor in the context of both its immediate 

“microenvironment” and the broader environment 

of the body, and the whole person in the context 

of the behavioral, social, and environmental factors 

that influence cancer. 

We must ensure the application of our research knowledge to cancer care. NCI will collaborate with other 

agencies and private groups to eliminate unnecessary delays, along the pathway of discoverydevelopment-delivery for lifesaving interventions 

against cancer. While adhering to our NCI mandate, 

I am committing NCI to rigorously disseminate 

our research results, with special emphasis on our 

comprehensive Cancer Centers, to inform both 

clinical practice and public health with state-ofthe-art science. 

For Fiscal Year 2004, we are adding to our plan and 

budget proposal new initiatives to better understand 

the tumor microenvironment, cancer survivorship, 

and the interface of aging and cancer. We also place 

greater emphasis on translational research to move 

potential preventive, diagnostic, and therapeutic 

interventions into clinical trials and to integrate 

more effective cancer care and control interventions 

into clinical practice and public health programs. 

Our intramural research program will set a new 

standard for exemplary translational research. 

We are working to find new and more effective ways 

to collaborate aggressively both inside and outside 

of the National Institutes of Health, especially 

through partnerships with our Nation’s community 

of scientists, physicians, nurses, cancer survivors, 

and other advocates. 

We will redouble our efforts to eliminate disparities by 

ensuring that every American, regardless of race, 

income, and gender, has access to high quality 

and timely cancer prevention, screening, diagnosis, 

and treatment. And we will strive to understand 

and reduce biologic, socioeconomic, and cultural 

disparities in the incidence of cancer among 

diverse population groups. 

We will also ask that our programs be examined 

against the criteria recently established in 

support of the President’s Management Agenda, 

and I am committed to making sure that progress 

toward the goals described in the following pages is 

evaluated against the objectives of sound and 

comprehensive science. 

Andrew C. von Eschenbach, M.D. 

Director


National Cancer Institute


October 2002


1DIRECTOR’S MESSAGE 

A Plan and Budget Proposal for Fiscal Year 2004 
Table of Contents 

1 

3 

8 

14 

18 

24 

26 

27 

32 

36 

42 

46 

48 

49 

55 

60 

65 

72 

77 

78 

84 

88 

94 

31 

83 

41 

54 

70 

23 

93 

Director’s Message 

Executive Summary 

Highlights of Progress 

Our Role in Cancer Research 

National Agendas for Disease-Specific Research 

Planning and Priority Setting for Cancer Research 

Fiscal Year 2004 Budget Request 

Building the Nation’s Cancer Research Capacity 

Enhancing Investigator-Initiated Research 


Expanding the Capacity of Centers, Networks, and Consortia 


National Clinical Trials Program in Treatment and Prevention


Developing Bioinformatics for Cancer Research 


The Interface of Aging and Cancer 

Advancing Discovery and Its Application 

Genes and the Environment 


Signatures of the Cancer Cell and Its Microenvironment 


Molecular Targets of Prevention and Treatment 


Cancer Imaging and Molecular Sensing 


Cancer Communications 


Addressing Areas of Public Health Emphasis 

Improving the Quality of Cancer Care 


Reducing Cancer-Related Health Disparities 


Cancer Survivorship: Improving Treatment Outcomes and Quality of Life 


Research on Tobacco and Tobacco-Related Cancers 


Progress Reports 

Increased Investment Strengthens Research Training and Career Development 


Sustained Investment in Studying Cancer Trends Improves 


Knowledge and Understanding of Cancer 


Spotlights on Research 

Drug Discovery and Development: A Life Saving Investment 

Genes and Proteins: Profiles of Hope 

Story of Discovery 

Harnessing Apoptosis to Destroy Cancer Cells 

People’s Stories 

Esophageal Cancer 


Adult Survivors of Childhood Cancers 


2 The Nation’s Investment in Cancer Research 
Executive Summary


The goal of the National Cancer Institute is to achieve a future when all cancers are controlled or 

eliminated, by stimulating and supporting research and its application. We provide vision and leadership 

to the cancer community as we strive to more fully integrate discovery activities through interdisciplinary collaborations, to accelerate the development of interventions and new technology through 

translational research, and to ensure the delivery of these interventions through clinical and public 

health programs. 

Recent reports indicate that overall cancer death 

rates decreased from 1993 to 1999, while rates of 

cancer incidence stabilized over a similar timeframe. More people are getting screened for breast, 

cervical, and colorectal cancers, and more practitioners are adopting state-of-the-art cancer treatments. 

But we still need to employ greater efforts to 

reduce tobacco use, weight gain, and sun exposure 

and to increase physical activity. We also need to 

reduce rates of some cancers that are still on the 

rise. These include non-Hodgkin’s lymphoma, 

melanoma, cancers of the liver and esophagus, 

as well as breast and lung cancer in women. 

Trends in various population groups differ substantially by cancer site, sex, and race, and we must 

redouble our efforts to eliminate persistent cancerrelated health disparities. Because of the increasing 

size of the population and the growing proportion of 

older persons, researchers expect the cancer burden 

in the United States to increase substantially over 

the next several decades. Our changing age structure 

will require aggressive strategies for cancer 

prevention and early detection, social support, 

treatment and medical care, clinical trial design and 

enrollment, research, and surveillance. In addition, 

access to supportive, palliative, and general medical 

services must be optimized. 

The framework for the NCI budget is built on 

priorities that are broadly applicable to cancer 

research and development and our ability to prevent, control, detect and quickly diagnose, treat, 

and care for patients with all types of cancer. Within 

that framework, NCI also carries out an extensive 

program to develop National Agendas for 

Disease-Specific Research, charting the course 

primarily through advice from experts in Progress 

Review Groups (PRGs). We address PRG recom­


mendations by modifying and supplementing


existing research programs, encouraging scientists


to apply for disease-specific research funding, 


and developing new initiatives when needed. 


NCI supports research focused on specific types of


cancer through broad-based initiatives such as the


Specialized Programs of Research Excellence, the


Early Detection Research Network, the Innovative


Molecular Analysis Technologies Program, and the


Mouse Models of Human Cancers Consortium.


Funding for disease-specific research is an integral


part of many NCI initiatives.


Our total proposed Fiscal Year 2004 Budget


Request is $5,986,000,000. This represents an


increase of $1,348,131,000 over the Fiscal Year


2003 President’s Budget. Of this increase,


$294,014,000 will be provided to continue 


NCI commitments into 2004 (Core Budget). 


An additional $577,517,000 will be used for


Building the Nation’s Cancer Research


Capacity, $266,250,000 will support 


Advancing Discovery and Its Application, 


and $210,350,000 will fund research for


Addressing Areas of Public Health Emphasis.


While we are not requesting increases in funding


for Cancer Research Training and Career


Development or for Studying Emerging Trends,


these continue to be priorities for NCI.


Building the Nation’s Cancer 

Research Capacity 

Bringing the benefits of cancer research to the 

American people depends on building and sustaining the strong research mechanisms, support structures, and collaborations that enable us to pursue 

EXECUTIVE SUMMAR Y 

A Plan and Budget Proposal for Fiscal Year 2004 3
rapidly evolving discoveries. NCI must provide 

the vision, creative environment, and diverse 

resources needed to ensure a fast paced and synergistic flow of innovative thinking among scientists 

in disparate scientific disciplines. We must also 

leverage our collaborations with other government 

agencies, academia, and industry, focused on steering major breakthroughs toward the delivery of 

effective cancer interventions. 

Investigator-Initiated Research has always been 

the driving force behind advances in biomedical 

research. Access to powerful new tools, special 

resources, and scientific collaborations are increasingly important to an investigator’s ability to develop the independent concepts that lead to discovery 

and translate results to targeted drugs and treatment. NCI aims to balance the flow of resources to 

ensure that the best ideas are promoted through 

flexible funding options such as cooperative agreements, seed funds, and supplemental funds for 

unanticipated opportunities. Compelling proposals 

are supported with exceptions funding, particularly 

those suggesting novel approaches. Expert NCI 

advisory panels and Progress Review Groups continue to identify priority research and recommend 

funding. With increased resources in 2004, we will be 

able to fund the top 35 percent of competing grant 

applications using flexible criteria and continue to 

allocate the first 80 to 90 percent of available funds 

for research project grants through conventional 

selection processes, while ensuring that proposals 

from new investigators are also funded. 

NCI-supported Centers, Networks, and 

Consortia encourage the interdisciplinary collaborations needed to address the “big picture” problems in cancer research and integrate clinical observations with research investigation. The rapid pace 

of scientific and technological discovery requires 

that scientists of diverse backgrounds work together to share information and resources. In 2004, NCI 

will use new funding to increase the number and 

geographic distribution of Cancer Centers, providing service to regional communities in addition to 

expanding crosscutting research capacity. Cancer 

Centers will serve as platforms to support new 

technology development, improve informatics 

capabilities, and conduct more clinical and population research. Specialized Programs of Research 

Excellence will be expanded based on needs for 

disease-specific translational research. Underserved 

and minority populations will have improved access 

to the newest trials and state-of-the-art care through 

partnerships with NCI-designated Cancer Centers, 

Minority-Serving Institutions, and NCI Special 

Populations Networks. 

NCI’s National Clinical Trials Program in 

Treatment and Prevention provides a versatile 

system to safely move emerging cancer interventions into health care delivery. NCI’s challenge is 

to provide the leadership demanded by the emerging paradigm of molecular targeted therapy in 

cancer treatment and prevention. With adequate 

funding in 2004, NCI will be poised to identify 

the most important questions that can be addressed 

through clinical trials; create the flexible mechanisms and support that will bring together basic 

scientists and clinicians to find the answers; fund 

tissue and specimen banks; help develop surrogate 

endpoints for use in small translational trials; move 

the most promising interventions into large and 

easily accessible trials; and simplify administration 

activities while increasing patient accrual, to substantially increase the number of new treatments 

and other interventions being evaluated. With 

sufficient funding, we can make state-of-the-art 

clinical trials and the ensuing discoveries available 

to all who can benefit from them. 

Bioinformatics for Cancer Research will help 

us harness the growing flood of scientific information using NCI’s systems for resource sharing and 

for translating pioneering research into better medicine. Virtual experiments will use data from multiple sources. We will generate hypotheses and 

create and manage more knowledge faster with 

systems that standardize, support, and integrate 

information from our diverse research. caCORE, a 

standards-based cancer knowledge resource, makes 

possible “in silico” experiments with the Cancer 

Models Database, Cancer Genome Anatomy 

Projects, and the Cancer Therapy Evaluation 

Program. For example, participants in the Cancer 

Molecular Analysis Project locate and assess possible molecular targets, find therapeutic agents, 

screen for toxicity, and identify clinical trials. 

Bioinformatics holds impressive potential for facilitating cancer diagnosis, as demonstrated in the 

recent marriage of proteomics and artificial intelligence that resulted in a promising ovarian cancerscreening test. In 2004, NCI will use new funds to 

expand our own informatics infrastructure and the 

informatics capacity of the research community. 

4 The Nation’s Investment in Cancer Research 
Advancing Discovery and 

Its Application 

Increased investment in broad scientific opportunities and emergent fields of research that lie 

beyond the size and scope of our current research 

activities allow us to accelerate the pace of discovery. Better understanding our audiences and their 

needs allows us to facilitate application of research 

results in the clinic and public health programs, to 

benefit all people affected by or at risk for cancer. 

The study of Genes and the Environment 

increases our understanding of the interplay 

between individual inherited susceptibility to cancer and environmental risk factors, enabling the 

development of more effective approaches to cancer prevention, early detection, and treatment. 

NCI is investing in this area through large-scale 

collaborations, such as the Cohort Consortium, by 

bringing epidemiologists, genomicists, and other 

investigators together to pool data and resources 

for large population studies. NCI Cancer Family 

Registries provide resources for the characterization of predisposing genes found in families at 

high risk for cancer. In 2004, NCI will use new 

funding to identify additional environmental risk 

factors and susceptibility genes and determine 

their interactions in cancer causation; identify 

genes in high-risk families and investigate how 

other genes and environmental factors modify 

them; and support collaborative studies of the 

clinical, behavioral, and societal issues associated 

with cancer susceptibility. 

All cells have “molecular signatures” – unique, 

identifiable characteristics related to a cell’s function in the body. As a normal cell becomes malignant, its signature changes and this change 

becomes a signal of the presence of cancer. 

Research on Signatures of the Cancer Cell and 

Its Microenvironment focuses on identifying the 

signatures of both cancer cells and “co-conspirator” 

cells in the surrounding microenvironment that 

interact with cancer cells to encourage tumor 

growth. With new technologies, scientists are reading cancer-associated signatures and using this 

information to detect cancers at their earliest stage, 

to diagnose and classify tumors according to their 

molecular profiles, and to devise treatments that 

selectively target molecular signatures. Several 

large initiatives are already making important 

progress in these areas. New funding in 2004 will 

be used to define and characterize the molecular 

signatures of cells in the cancer microenvironment 

at various points during cancer initiation and progression; to define how communication among cancer 

cells, surrounding cells, and immune cells controls 

or promotes tumor growth; and to create targeted 

interventions based on this new knowledge. 

Our ability to decipher the molecular basis of cancer has launched an exciting new era in biomedical 

research as we hone in on Molecular Targets of 

Prevention and Treatment. Researchers are 

directing a new generation of low toxicity, high 

efficacy agents against the molecular features, or 

targets, that cause tumor growth. NCI is using a 

multi-disciplinary approach to discover ways to trigger the cancer cell to revert to normal, stop replicating itself, or self-destruct. Other strategies harness 

the immune system to combat the cancer or prevent surrounding tissues (the “tumor microenvironment”) from supporting cancer growth. NCI will 

use new funding in 2004 to characterize potential 

targets; support basic and clinical research to validate drugs developed to hit the targets and move 

them into clinical use; investigate combinations of 

radiation therapy with molecular therapeutics; and 

develop the next generation of cancer vaccines. 

This work will speed development of interventions 

against cancer, based on the unique molecular 

characteristics of each patient’s tumor. 

Investment in Cancer Imaging and Molecular 

Sensing has dramatically improved cancer detection, diagnosis, and treatment. Experimental, 

molecule-size biosensors that can be injected into 

the bloodstream promise even more options for 

patient care. NCI’s challenge is to improve imaging 

and biosensor technologies to ensure earlier, more 

accurate cancer diagnoses, individualize therapies, 

use fewer invasive interventions, and improve 

patient monitoring. Accordingly, NCI is improving 

functional imaging, developing molecular and 

digital imaging databases, building micro-imaging 

techniques for animal research, and supporting 

biosensor research. Through clinical trials and 

public-private partnerships, we are moving promising imaging advances from discovery and development to clinical use. With new funding in 2004, 

NCI will be able to expand development of novel 

imaging agents and devices; increase clinical trials 

of imaging technologies, such as the National Lung 

Screening Trial; integrate functional imaging 

methods into therapeutic clinical trials; advance 

EXECUTIVE SUMMAR Y 

A Plan and Budget Proposal for Fiscal Year 2004 5
image-guided interventions; and stimulate research 

on biosensors. Significant advances in these areas 

will increasingly save and improve lives. 

Cancer Communications empowers people to 

make informed cancer-related decisions and adopt 

behaviors to improve their health. NCI is working 

to optimize the use of communications tools to 

meet the information needs of all groups while 

building strategies to enhance the important interaction between patients and their doctors and 

nurses. Lives are saved through communication 

interventions that decrease or prevent smoking, 

influence good nutritional choices, and increase 

the number of people who are screened to detect 

cancer early. Enhanced NCI databases and Web 

sites include user friendly topical formats and clinical trials information. In 2004, NCI plans to establish new data collection and analysis strategies, 

including the first national health communications 

survey of U.S. populations; accelerate the pace of 

research and development of communications 

interventions; increase access to and use of cancer 

information; and improve our understanding of 

and ability to effectively move research results into 

clinical practice and public health programs. 

Addressing Areas of 

Public Health Emphasis 

Progress against cancer takes place not only in the 

laboratory and the physician’s office, but also within broad public health programs. NCI has identified four areas to more fully address cancer care 

and its consequences and translate research into 

full application for people affected by cancer. 

Improving the Quality of Cancer Care is a 

major national concern. Barriers to high quality 

care include system and financial limitations, 

proximity of healthcare facilities, available 

education and information, and physician and 

patient biases. To address these concerns, NCI is 

helping to ensure that the best available scientific 

evidence guides cancer care decision making. NCI 

is supporting the Cancer Care Outcomes Research 

and Surveillance Consortium and other studies to 

strengthen the science base for understanding 

palliative care and symptom management 

and end-of-life distress as well as examining 

depression in cancer patients. With funding 

increases in 2004, NCI will engage in activities to 

improve methodology and measurement of patient 

outcomes; support innovative research on the diffusion, quality, and outcomes of cancer interventions and its translation to best practices in patient 

care; enhance quality-of-care research within the 

NCI clinical trials program; strengthen cancer 

communications; and inform science-based 

Federal decision making. 

Effectively Reducing Cancer-Related Health 

Disparities requires new understanding to explain 

social, cultural, environmental, biological, and 

behavioral determinants of cancer, the interactions 

among them, and the mechanisms by which they 

contribute to disparities in cancer care and prevention. NCI continues to address disparities among 

all population groups through numerous initiatives 

such as the establishment of new centers focused 

on disparities research, the Cancer Prevention 

Fellowship Program, and the implementation of 

a landmark study to determine factors that contribute to cancer among groups hardest hit by the 

disease. In 2004, we will use funding increases to 

expand our research on the causes of health disparities in cancer; define and monitor disparities; 

develop and implement new policy, community, 

and clinical interventions, and evaluate their 

impact; and expand minority investigator competition for, and minority population involvement in, 

health disparities research and clinical trials. 

Through statistics on Cancer Survivorship, we 

are beginning to see the fruits of the “War on 

Cancer” launched in 1971. Once almost uniformly 

fatal, cancer has become a chronic illness for many 

and, for growing numbers of people, a curable disease. Fewer deaths from other diseases and the 

aging of the population also contribute to the rising number of cancer survivors. However, we have 

many questions about the health status and quality 

of life for most patients in their post-treatment 

years. What is clear is that most of our current 

treatments will produce some measure of adversity. NCI is initiating a focused effort in 2004 to 

understand the mechanisms that affect a cancer 

patient’s response to disease, treatment, and recovery; develop tools to assess quality of life following 

treatment; track outcomes for cancer survivors; 

disseminate clinical guidelines; and expand the 

scientific base for understanding the adverse late 

effects of current and new cancer treatments. 

6 The Nation’s Investment in Cancer Research 
Research on Tobacco and Tobacco-Related 

Cancers is driven by the devastating impact of 

tobacco use and tobacco exposure on the incidence 

of cancer. Tobacco use causes more premature 

death (approximately 430,000 per year in the 

United States) than do all drugs of abuse combined. NCI research is focused on improving 

understanding of tobacco-related addiction and 

carcinogenesis, including the role of genetic and 

environmental factors in smoking initiation, 

persistence, and relapse. Through several new 

initiatives, including the Lung Cancer Screening 

Study as well as preclinical and clinical studies to 

identify more potent agents for cancer prevention, 

NCI-supported research is targeting the health 

needs of current and former smokers. NCI will 

use new funds in 2004 to expand the infrastructure 

needed to conduct a vigorous research program; 

support investigations to understand and treat 

tobacco use and addiction; and apply cutting edge 

research to better understand and treat tobaccorelated cancers. 

Planning at NCI Includes the Larger Cancer 

Community 

Each year, countless people at NCI, on our advisory 

boards, in other government agencies, and in research, 

professional, and advocacy organizations around the 

country provide their insights, perspectives, and expertise for the development of this document. Members of 

the Office of Science Planning and Assessment provide 

leadership and guidance for plan development from 

conceptualization to production. They work alongside 

the core group of NCI leaders who serve as Champions 

for the various priority areas and with the Office of 

Budget and Financial Management. Numerous other 

people at NCI review drafts, provide background information, and identify new areas to explore. In 2001, 

some 40 individuals and organizations inside and outside NCI responded to our sweeping solicitation to the 

cancer community for suggestions about new scientific 

priority areas (Extraordinary Opportunities). In the summer of 2002, a similar number of people outside of NCI 

responded to our request for input to a draft of this document. All of these contributions have been invaluable 

in helping us develop a plan for Fiscal Year 2004 that 

captures the opportunities, challenges the community to 

new heights, and brings us closer to our goal to control 

or eliminate all cancers. See page 100 for our acknowledgments list of people and organizations who contributed to this document. 

EXECUTIVE SUMMAR Y 

A Plan and Budget Proposal for Fiscal Year 2004 7

NCI's Budget Request for Fiscal Year 2004 

(dollars in thousands) 

Fiscal Year 2003 President's Budget $ 

Increase to Core Budget 294,014 

Capacity Building Increase 

Enhancing Investigator-Initiated Research 69,887 

Expanding the Capacity of Centers, Networks, and Consortia 79,530 

National Clinical Trials Program in Treatment and Prevention 340,100 

Developing Bioinformatics for Cancer Research 88,000 

Subtotal Capacity Building 577,517 

Discovery and Application Increase 

Genes and the Environment 51,800 

Signatures of the Cancer Cell and Its Microenvironment 41,200 

Molecular Targets of Prevention and Treatment 54,800 

Cancer Imaging and Molecular Sensing 78,700 

Cancer Communications 39,750 

Subtotal Discovery and Application 266,250 

Public Health Emphasis Increase 

Improving the Quality of Cancer Care 27,000 

Reducing Cancer-Related Health Disparities 61,350 

Cancer Survivorship 46,000 

Research on Tobacco and Tobacco-Related Cancers 76,000 

Subtotal Public Health Emphasis 210,350 

Total FY 2004 Budget Request $5,986,000 

4,637,869 
8 The Nation’s Investment in Cancer Research 

Trends in Research and Care 

NCI Releases the Cancer Progress Report. 

To build on areas of greatest success and pinpoint 

areas of greatest need, NCI is working with many 

partners to stay abreast of progress in cancer 

research and care in the United States. NCI’s 

Cancer Progress Report, 

1 first published in 

December 2001, describes the Nation’s progress in 

reducing the cancer burden, encompassing the continuum from prevention to deaths from specific 

cancers. Also reflected are declines in certain 

behaviors that cause cancer, especially cigarette 

smoking by adults. More people are getting 

screened for breast, cervical, and colorectal cancers, 

and more practitioners are adopting state-of-the-art 

cancer treatments. At the same time, work needs to 

be done to reduce rates of some cancers that are 

still on the rise. These include non-Hodgkin’s 

lymphoma, melanoma, cancers of the liver and 

esophagus, as well as breast and lung cancer in 

women. Greater efforts also are needed to reduce 

tobacco use, weight gain, and sun exposure and to 

increase physical activity. We must also redouble 

our efforts to eliminate persistent cancer-related 

health disparities among population groups. 

Changing Age Structure of the United States 

Will Help Guide the Future of Cancer 

Research and Care. The Annual Report to the 

Nation on the Status of Cancer, 1973-1999, 

Featuring Implications of Age and Aging on the U.S. 

Cancer Burden,2 was released in May of 2002. The 

report is encouraging. Overall cancer death rates 

decreased from 1993 to 1999, while rates of cancer 

incidence stabilized over a similar timeframe. 

However, trends in various populations groups differed substantially — e.g. by cancer site, sex, and 

race. Most notably, because of increasing population 

and the growing proportion of older persons, 

researchers expect the cancer burden in the United 

States to increase substantially over the next several 

decades. Our changing age structure will require 

aggressive strategies for cancer prevention and early 

detection, social support, treatment and medical 

care, clinical trial design and enrollment, research, 

and surveillance. In addition, access to supportive, 

palliative, and general medical services must be 

optimized. 

Prevention and Control 

Smoking Cessation Drug May Help Address 

Smoking-Related Health Disparities. In a recent 

landmark study, investigators found that bupropion, 

a promising smoking cessation drug previously 

studied mostly in White populations, is effective 

in helping African Americans quit smoking. 

Bupropion also seemed to curb both weight gain 

and feelings of depression among study participants, key indicators of whether a person will return 

to smoking. The success of this treatment is especially significant given that smoking rates are higher 

for African Americans than for the overall population of the United States. For example, close to half 

of African Americans who live in inner cities smoke 

compared to about one quarter of the general 

population. Smoking is the leading cause of lung 

cancer and a major risk factor for other cancers as 

well as heart disease, respiratory disorders, and 

other diseases prevalent in African American groups. 

Researchers hope that a successful smoking 

cessation program, aided by bupropion, may help 

reduce smoking-related health disparities experiHighlights of Progress 

1 progressreport.cancer.gov 2 Prepared by the National Cancer Institute, the Centers for Disease Control and Prevention, the National Center for Health Statistics, the American Cancer 

Society, and the North American Association of Central Cancer Registries. seer.cancer.gov/reportcard 

Every year thousands of NCI-supported research projects move us closer to a time when cancer 

can be controlled or eliminated. The recent doubling of NCI’s budget has been instrumental in funding 

numerous studies across the cancer continuum and from fundamental laboratory research to patient 

care. These highlights of recent progress provide a snapshot of the breadth of our research advances. 
HIGHLIGHTS OF PROGRESS 

A Plan and Budget Proposal for Fiscal Year 2004 9

enced by African Americans as well as the overall 

cancer burden caused by tobacco use. 

Potential of Dietary Aids for Cancer Prevention 

Is Complex. Over the years, many studies have 

examined how what we eat or drink affects our risk 

of developing cancer. The sometimes conflicting 

results point to the need for large, careful studies to 

clarify some of these findings. In one recent study, 

with tens of thousands of participants, investigators 

discovered that both men and women could reduce 

their risk of developing cancer of the distal colon by 

consuming high levels of calcium daily. A similar 

study showed that high levels of calcium and dairy 

products substantially increase the risk for prostate 

cancer, while lycopene, a component of tomatoes, 

provided some protection against prostate cancer. 

The finding that calcium can reduce the risk of one 

cancer while increasing the risk of another illustrates 

the complexity of the interaction between diet and 

cancer. Further study is needed before clear advice 

can be communicated to the public about the usefulness of calcium for cancer prevention. 

Oophorectomy after Childbearing Years Lowers 

Cancer Risk in Women with BRCA Mutations. 

Women who were born with certain mutations to the 

genes BRCA1 and BRCA2, are more likely to develop 

breast and/or ovarian cancer, and at a younger age 

than the general population. Based on the findings 

of a number of small studies, physicians have been 

recommending that women with these mutations 

undergo prophylactic oophorectomy (removal of the 

ovaries), once they have finished having children. 

Recently completed large studies have validated this 

practice to reduce cancer risk. In an NCI-supported 

study, ovarian cancer risk was reduced by a striking 

96 percent and breast cancer risk was reduced by 

about 50 percent. Side effects brought on by premature menopause are manageable by medication. 

The researchers found no evidence to suggest that 

the ovaries should be removed before the childbearing years. 

Other cancer prevention and control highlights 

in this document: 

■ Genetic signatures and risk factors for pancreatic 

cancer, page 21 

■ Risk factors for esophageal cancer, page 23 

■ Arthritis drug and prevention of colon polyps, 

page 36 

■ Aspirin for preventing colon cancer, page 40 

■ Genetic signature and effectiveness of 

bupropion, pages 94-95 

■ Key factors in adolescent cigarette use, page 95 

Detection, Diagnosis, and 

Prognosis 

New Blood Test for Early Detection of Prostate 

Cancer Looks Promising. To screen for prostate 

cancer, doctors currently use a blood test to measure 

the levels of a protein called prostate-specific antigen (PSA), which is consistently elevated in men 

with prostate cancer. However, since PSA is sometimes elevated even in the absence of cancer, a follow-up biopsy must be performed if the PSA test is 

positive. The PSA test is quite helpful to many men 

by detecting their cancer in its earliest stages. The 

down side is that a number of men without the disease are subjected to biopsy, and associated anxiety, 

to rule out cancer. To address this concern, 

researchers used the emerging technology of protein 

profiling3 to fashion a new blood test. The new test 

uses computer-based artificial intelligence to study 

the dynamic patterns of nine separate proteins in 

the blood. , this test correctly 

identified most men with prostate cancer and misclassified far fewer men without the disease than 

could be hoped for with the PSA test. With further 

development, this new test may lead to a more 

accurate means to detect and diagnose prostate 

cancer at a very early stage, with fewer false 

positives and unnecessary biopsies. 

SPORE4 Study Suggests New Molecular Test 

Useful for Prognosis of Colorectal Cancer. 

To estimate the chance that colorectal cancer might 

recur after surgery, health professionals must examine small amounts of tumor tissue under the microscope. This is called histopathological staging. 

Many scientists are looking for molecular markers, 

such as suspicious abnormalities in tumor DNA, to 

develop a more reliable prognostic tool. Previously, 

scientists discovered that patients with allelic imbalance5 in certain chromosomes of the tumor tend to 

have a poorer prognosis. Until recently, however, it 

has been very difficult to accurately measure allelic 

imbalance in tumor tissue. Now, investigators have 

3 For more information on protein profiling, see page 54. 

4 Specialized Programs of Research Excellence. For description see page 32 . 

5 Chromosomes come in pairs that are typically nearly identical in makeup. 

comprise what we call “chromosome 8.” Sometimes errors occur that make one chromosome of a pair substantially different from the 

other. This is known as 

In preliminary study

For example chromosome 8p and chromosome 8q together 

“allelic imbalance.” 
10 The Nation’s Investment in Cancer Research 

developed a highly sensitive test using a technique 

called “digital SNP analysis.” This new test 

measures the allelic imbalance in two colon cancerassociated chromosomes, 8 and 18. They found 

that, after five years of follow up, cancer recurred in 

42 percent of patients with allelic imbalance in both 

chromosomes and in 26 percent of those with one 

chromosome affected. In contrast, all patients with 

no detectable allelic imbalance in chromosomes 8 

or 18 remained disease free after five years. Since 

routine histopathological staging would have mistakenly predicted recurrence in at least some of 

these disease-free patients, this new test appears to 

provide an improved prognostic indicator of colorectal cancer. Further research must be done to 

show whether this technique will work as well for 

other cancer sites. 

Ovarian Cancer patients with BRCA Mutation 

Have Better Survival than Non-Carriers. 

Women who inherit mutations to the BRCA1 or 

BRCA2 gene, have a greater risk of developing 

ovarian cancer. However, until recently, researchers 

could not predict whether women with these mutations would fare better, the same, or worse than 

other women with ovarian cancer. To examine this 

issue, researchers studied the medical records of 

almost 900 newly diagnosed ovarian cancer patients 

with inherited BRCA mutations and followed their 

progress for five years.6 Investigators compared the 

progress of these women to that of patients who 

had no BRCA mutation. On average, the patients 

with BRCA mutations survived for about 53.4 

months, almost 20 months longer than women 

without the mutations. This survival advantage was 

not due to earlier detection, but seems to reflect a 

difference in the pattern of the disease in women 

with and without BRCA mutations. The mechanism 

of this phenomenon is not known. Further follow 

up in this continuing study should reveal whether 

the better survival of BRCA mutation carriers is 

long-term or limited to the first few years of the 

disease. 

Other detection, diagnosis, and prognosis 

highlights in this document: 

■ Genetic signatures and diagnosis of acute 

lymphoblastic leukemia, pages 44 and 54 

■ Blood test of protein patterns and 

early detection of ovarian cancer, pages 45, 

54, and 59 

■ Gene expression array for prognosis of diffuse 

large-B cell lymphoma, page 54 

■ Signatures of lung cancer sub-classes, page 59 

Treatment 

New Approach to Immunotherapy for 

Advanced Melanoma Results in Dramatic 

Tumor Regression. In a recent study of 

melanoma7 patients, researchers discovered a way to 

enhance the immune system’s natural, but weak, 

ability to attack cancer cells. Investigators began by 

collecting a small number of white blood cells from 

the tumors of each of 13 patients. From these, they 

isolated the cells that were most adept at attacking 

melanoma — those that could best recognize an 

antigen8 abundantly expressed on melanoma cells 

and to a lesser extent on normal melanocytes. They 

grew large quantities of these white blood cells and 

injected them back into each patient along with an 

immune-boosting protein. To prevent the patient’s 

naturally occurring white blood cells from crowding 

out the melanoma-attacking cells, investigators 

temporarily depleted the patient’s immune system 

with chemotherapy prior to injection. With this 

treatment regimen, six patients experienced dramatic regression of metastatic tumors. Surgeons 

removed the traces of tumors from two of these 

patients who have remained cancer free, one for 

over two years. In some patients, the melanomakilling cells also attacked normal melanocytes, 

resulting in patches of skin without pigmentation 

(a non-threatening condition known as vitiligo). 

Other side effects were treatable. This pioneering 

study establishes two landmark principles of cancer 

research. First, this unique approach to harnessing 

the immune system can be an effective treatment 

for patients with metastatic cancer. Secondly, naturally occurring antigens that are over-expressed on 

cancer cells may provide useful immunotherapy targets for cancers such as prostate, breast, ovarian, 

and thyroid, since the organ function is either not 

necessary for survival or can readily be replaced. 

6 The study was performed in Israel where more women have the mutations, making it easier to conduct a large study. 7 Melanoma is cancer of the melanocytes, the pigment producing cells of the skin. It is almost always fatal once it spreads beyond the initial site. 8 An antigen is a protein or protein fragment located on the outside of a cell. 
HIGHLIGHTS OF PROGRESS 

A Plan and Budget Proposal for Fiscal Year 2004 11

SPORE Scientists Find Ways to Overcome 

Resistance to Tamoxifen for Breast Cancer 

Treatment. A subclass of breast cancer known as 

“estrogen receptor positive” (ER-positive) grows 

more aggressively when exposed to estrogen. 

The drug tamoxifen works well against ER-positive 

breast cancer by lowering estrogen levels in the 

body. However, scientists have been faced with the 

puzzle of why some women never respond to this 

drug and why in those who are helped, it often 

works only for a limited time. Also, high levels of a 

certain protein, HER-2, seem to make tumors more 

resistant to tamoxifen, but only in some women. In 

studying these problems, researchers found that 

another drug, fluvestrant, works against tumors that 

don’t respond to tamoxifen. Investigators also discovered that HER-2, by itself, does not interfere 

with tamoxifen. Only in women where HER-2 and 

a second protein, AIB1, are simultaneously elevated, 

were tumors resistant to tamoxifen. This research 

on the mechanisms of tamoxifen resistance is yielding new, more effective treatment approaches. 

The United States Food and Drug Administration 

recently approved fluvestrant for treatment of 

tamoxifen-resistant, ER-positive breast cancers, and 

scientists anticipate that further research on HER-2 

and AIB1 may open highly promising avenues for 

both diagnostic and therapeutic interventions. 

Molecularly Targeted Drug Slows Tumor 

Growth in Patients with Kidney Cancer. 

9 

Researchers have identified another promising 

molecularly targeted10 cancer treatment drug. In a 

recent clinical trial, the drug bevacizumab significantly slowed the growth of metastatic renal cancer 

in patients with advanced disease and no known 

treatment options. Patients given this drug showed 

no measurable tumor growth for about five months, 

as compared to two months in patients taking a 

placebo. Bevacizumab targets a protein, called 

VEGF, needed by the tumor to generate new blood 

vessels (angiogenesis) to bring oxygen and nutrients 

for growth. This study is an important first step 

toward showing that recent exciting laboratory 

advances in attacking cancer by thwarting angiogenesis will work in patients. More than 20 additional 

clinical trials are currently underway to evaluate 

bevacizumab as a cancer treatment, including Phase 

III trials for breast and colorectal cancers and Phase 

II trials for prostate, breast, colorectal, cervical, ovarian, pancreatic, and lung cancers, mesothelioma, 

and several types of leukemia. 

Experimental Drug Improves Survival of 

Patients with Advanced Colorectal Cancer. 

Researchers conducting a large clinical trial have 

discovered a new chemotherapy drug that, in combination with current drugs, appears to improve the 

survival of colorectal cancer patients. 

advanced colorectal cancer who were treated with 

the “FOLFOX4 regimen” (which includes the 

experimental drug oxaliplatin), lived about four 

months longer than patients receiving standard 

therapy, the “Saltz regimen.”11 Patients treated with 

FOLFOX4 responded better to their medication 

and tumors were slower to progress. Although many 

patients developed a neurotoxicity not seen with 

the Saltz regimen, severe side effects were significantly fewer overall. Furthermore, 71 percent of 

patients on FOLFOX4 were living after one year, 

compared to 58 percent of those on the Saltz regimen. These results are impressive for a disease that 

is the second leading cause of cancer death in the 

United States. As further tests are being conducted, 

the manufacturer of oxaliplatin is submitting data to 

the United States Food and Drug Administration 

for possible use of this drug as a second-line treatment for colorectal cancer. 

Other treatment highlights in this document: 

■ Tamoxifen following chemotherapy and 

breast cancer patients, page 37 

■ Methotrexate and T-cell acute lymphoblastic 

leukemia survival, page 37 

■ Gleevec (imatinib) and chronic myelogenous 

leukemia, page 37 

■ Gleevec (imatinib) and GIST, page 37 

■ Immunotoxin and hairy cell leukemia, page 64 

9 See also page 22. 

10 Molecularly targeted drugs are designed to interact with and disrupt certain molecular features that are critical to the survival of the cancer cell, 

without harming healthy tissues. 

11 FOLFOX4 regimen: 5-fluorouracil/leucovorin/oxaliplatin 

Patients with 

Saltz regimen: irinotecan/5-fluorouracil/leucovorin 
12 The Nation’s Investment in Cancer Research 

Understanding the 

Causes of Cancer 

SPORE Scientists Say Inherited BRCA2 

Mutations May Increase Risk for Pancreatic 

Cancer.

12 Scientists believe that 10 percent of all 

cases of pancreatic cancer are hereditary. However, 

although mutations have been found in the tumors 

of patients with non-hereditary pancreatic cancers, 

the major gene(s) responsible for inherited cases 

have yet to be discovered. Uncovering the causal 

mutations would provide a way to identify people 

who might benefit from special surveillance 

because of an increased genetic risk of developing 

this disease. In a recent study, investigators 

searched for suspicious mutations in the BRCA2 

gene of pancreatic patients who had at least three 

relatives with this disease. They discovered mutations likely to be involved in tumor development in 

5 out of 29 (or 17 percent) of patients in the study. 

Further research is needed to better define the risk 

of pancreatic, and other cancers, in patients with 

these mutations. Additional genetic as well as environmental factors may influence this risk. 

SPORE Study of Tumor Microenvironments 

Yields New Insights into Cancer. Unique molecular interactions occur between cancer cells and 

their surrounding tissues, the “tumor microenvironment.” For example, when healthy tissues of the 

body are invaded with cancer cells, they become 

inflamed and form fibrous, scar-like tissue — known 

as “desmoplastic tissue.” In certain tumors that 

penetrate into surrounding tissues as they grow 

(known as infiltrating tumors), this desmoplastic tissue comprises the bulk of the tumor, outpacing the 

actual cancer cells. Recently, a team of scientists 

characterized the patterns of genes expressed in 

the cancerous growth and the microenvironment of 

two types of infiltrating cancer — pancreatic and 

infiltrating breast cancer. They discovered a highly 

ordered, coordinated process of tumor invasion, 

involving four distinct kinds of tissue and structured molecular interactions between the cancer 

and its surrounding tissues. This kind of insight 

into how cancers interact with their microenvironment may lead to previously unimagined strategies 

for imaging, diagnosis by blood test, and drug 

development and delivery for pancreatic, infiltrative 

breast, and numerous other cancers.13 

Gene-Environment Interactions Are 

Identified for Non-Hodgkin’s Lymphoma. 

Despite much research, the relationship between 

exposures experienced by farm workers and nonHodgkin’s lymphoma (NHL) is unclear. However, 

past studies did not consider gene-environment 

interactions that might occur in some genetic subtypes of this disease. Because of the way statistical 

analysis works, when the genetic subtypes of NHL 

are not studied individually, real associations 

between farming exposures and NHL might remain 

hidden. Investigators recently reviewed the exposure 

data and studied NHL biopsies from about 200 

patients who had participated in a prior study. 

These researchers were able to identify a 

particular genetic subtype of NHL that appears to 

be susceptible to the effects of pesticides. Larger 

studies are needed to clarify the mechanisms 

behind this gene-environment interaction and to 

discover ways to intervene to prevent NHL. 

Survivorship 

African American Cancer Survivors Report 

Poorer Functional Health than Whites. 

Older and minority patients have been underrepresented in research of post-cancer treatment 

issues. Investigators interviewed 180 African 

American and White long-term breast, colorectal, 

and prostate cancer survivors to identify differences 

in reported health problems, illness symptoms, 

functional difficulties, health worries and concerns, 

and overall perceptions of health. Although African 

Americans did not report significantly more symptoms resulting from their cancer or its treatment, 

they did report a greater decrease in physical functioning, perhaps related to treatment. Older African 

Americans also reported less concern about development of second cancers, suggesting a need for 

targeted education about the importance of followup care and screening. Continued research is needed to understand post-cancer treatment issues 

among older and minority patients. 

Adult Survivors of Childhood Cancer Lack 

Detailed Knowledge of Their Past Illness. 

Childhood cancer cure rates have risen dramatically 

over the past few decades, creating a growing body 

of adult survivors who face long-term health risks 

related to their cancer and treatment. Researchers 

interviewed 635 adult survivors of childhood 

cancer to find out how much they knew about their 

12 See also page 21. 

13 See also Signatures of the Cancer Cell and Its Microenvironment, pages 55-59. 
HIGHLIGHTS OF PROGRESS 

A Plan and Budget Proposal for Fiscal Year 2004 13

previous illness and treatment. None of the survivors were able to give a detailed summary of their 

disease, including the name of their cancer, whether 

they received certain chemotherapy drugs, and the 

site or sites of radiation treatment. Only 35 percent 

of those interviewed realized that past treatments 

could cause serious health problems in the future. 

Such missing information could prevent survivors 

from understanding their need for special follow-up 

care and surveillance. This study highlights a need 

for educating childhood cancer survivors about their 

past illness and how it was treated. 

Smoking Rates Characterized among Childhood 

Cancer Survivors. Researchers are working to characterize smoking patterns among childhood cancer 

survivors, who are at high risk for tobacco-related 

health problems. A recent survey of almost 10,000 

adult survivors of childhood cancer showed that, 

although these survivors were less likely to smoke 

than the general population, 17 percent were current 

smokers, and 11 percent were former smokers. 

Survivors who had been diagnosed with cancer in 

later childhood were more likely to start smoking, as 

well as those with a lower household income and/or 

less education. African Americans and survivors having had either pulmonary related cancer treatment or 

brain radiation were less likely to smoke. Among survivors who did start smoking, some were more likely 

to continue smoking: those who were at least thirteen 

years old when beginning to smoke, those with less 

education, and those who had brain radiation. The 

information gained by this research will help craft 

needed interventions to prevent smoking and to promote quitting in this high-risk population. 

Other survivorship highlights in this document: 

■ Tool used for studies on the consequences of 

cancer treatment, page 92 

■ Chemotherapy dosage and congestive 

heart failure, page 92 

■ Lung cancer survivor quality of life, page 92 

■ Growth hormone replacement for children 

following treatment for leukemia, page 92 

■ Social interventions for breast cancer survivors, 

page 92 

Quality of Cancer Care 

Racial and Ethnic Minorities Receive Less 

Appropriate Cancer Treatment. Racial and 

ethnic minorities in the United States bear a disproportionate burden of invasive cancers and cancer 

deaths. African Americans, for example, are more 

likely to develop a number of cancers and are 33 

percent more likely than Whites to die of cancer. 

Hispanics are more likely to develop cervical cancer, and Asian/Pacific Islanders to develop stomach 

cancer. A group of investigators extensively 

reviewed published scientific studies to find out 

whether any of these disparities stem from access to 

or use of specific cancer treatments. Their review 

confirmed that racial differences are evident in who 

receives the best available primary, conservative 

(such as breast conserving), and adjuvant therapies. 

Those receiving inferior therapy were also more 

likely to relapse and die. These disparities could be 

explained in part by non-clinical factors, such as 

socioeconomic status, patient concerns about body 

image, age at diagnosis, the size of the hospital 

where surgery is performed, the number of previous 

surgeries performed by the surgeon, geographic 

location, and insurance coverage. Patient preferences and decisions also played a part. 

Rate of Complications from Prostate Surgery 

Decreases with Number Performed. 

For many cancers requiring surgery, patient survival 

is better when the surgery is conducted at hospitals 

and/or by surgeons that perform the highest volume 

of this operation. Although this is not true for 

patients receiving prostate cancer surgery, for which 

survival is high overall, researchers wondered 

whether the choice of hospitals or surgeons might 

affect postoperative morbidity (e.g. urinary complications, incontinence). Investigators discovered that 

those men who underwent removal of the prostate 

at hospitals and by surgeons who performed a high 

volume of this surgery, experienced fewer 

postoperative and late urinary complications. 

The researchers point out a need for more careful 

scrutiny of adverse outcomes to reduce the burden 

of suffering among patients who undergo surgery 

for prostate cancer. 

Other quality of care 

highlights in this document: 

■ Social factors and survival among African 

American patients with advanced non-small 

cell lung cancer, page 85 

■ Educational interventions and cervical screening 

within the Chinese-American population, 

page 85 

■ African American men and risk for advanced 

prostate cancer, page 85 
Our Role in Cancer Research


The National Cancer Institute’s goal is to achieve a future when all cancers are controlled or 


eliminated by stimulating and supporting scientific discovery and its application. As the leader of the


National Cancer Program, we provide vision and leadership to the cancer community. We work to: 


■ More fully integrate discovery activities through interdisciplinary collaborations.


■ Accelerate development of interventions and new technology through translational research.


■ Ensure the delivery of these interventions for application in the clinic and public health programs. 


Integrate Accelerate 

DISCOVERY DEVELOPMENT 

Interdisciplinary Translational 

Science Research 

Partnerships & 

Collaborations 

Ensure


DELIVERYApplication in the Clinic &


Public Health Programs


Scientific Discovery 

NCI supports a broad range of research to expand 

scientific discovery at the molecular and cellular 

level, within a cell’s microenvironment, and in relation to human and environmental factors that influence cancer development and progression, and the 

patient experience. These insights provide the platforms on which to accomplish improvements in prevention, control, early detection and diagnosis, 

treatment, and post-treatment care. 

Each year, almost 5,000 principal investigators 

lead research projects that result in better ways to 

combat cancer. These scientists conduct studies at 

NCI and at nearly 650 universities, hospitals, and 

other sites in nearly every state in the Nation and in 

more than 20 foreign countries. Intramural research 

activities serve as hubs for new development 

through cutting edge basic, clinical, and epidemiological research. Extramural program experts 

provide guidance and oversight for research conducted at universities, teaching hospitals, and other 

organizations. Proposals submitted by extramural 

investigators are selected for funding by peer 

review, a rigorous process by which scientific 

experts evaluate new proposals and recommend 

the most scientifically meritorious for funding. 

Some studies involve basic laboratory research on 

genomics, proteomics, and molecular interactions. 

Others help us gain understanding of cancer in specific populations, such as former smokers, to better 

understand cancer risks related to environmental 

and lifestyle factors. 

In addition to direct research funding, NCI offers 

the Nation’s cancer scientists a variety of useful 

research services and tools. NCI-supported 

Cancer Centers and Centers of Research 

Excellence such as the In Vivo Cellular and 

Molecular Imaging Centers and the Centers of 

Excellence in Cancer Communications Research 

provide the kind of interdisciplinary environments 

required for special projects. The Transdisciplinary 

Tobacco Use Research Centers are supporting a 

broad array of studies on nicotine addiction and 

genetic and environmental factors related to smoking. Resources such as tissue samples, statistics on 

cancer incidence and mortality, databases of genetic 

information, imaging databases, and software for 

analyzing statistical and genetic data1 are made 

available at little or no cost. Consortia like the 

Mouse Models of Human Cancers Consortium 

allow scientists from around the world to share 

their expertise and resources in creating strains 

of mice that develop cancers similar to those seen 

in humans, making widely available an invaluable 

tool for cancer researchers. 

14 

1 For a directory, go to cancer.gov/resources. 

The Nation’s Investment in Cancer Research 
Intervention Development 

In addition to promoting integration and the 

interdisciplinary environment required to support 

today’s cancer scientists, NCI also uses collaborative platforms for translational research and 

intervention development. Translating basic 

research into interventions almost inevitably means 

developing new technologies or transforming those 

that we have been using. Thus, a new tool that first 

helps us to understand cancer may eventually be 

improved and distributed to help us diagnose it, 

and then may be advanced further still to help us 

treat it. For example, recent advances in bioinformatics and the related explosion of technology for 

genomics and proteomics research are dramatically 

accelerating the rate with which we can process 

large amounts of information for cancer screening 

and diagnosis. Likewise, new molecular imaging 

and biosensing technologies are opening doors to 

faster, more accurate detection and diagnosis, facilitating more accurate image-guided therapies, and 

making it possible to monitor treatment outcomes 

in real time. Similarly, nanotechnology promises to 

further expand the options for precisely detecting, 

diagnosing, treating, and monitoring cancer. 

To ensure that we use public funds to greatest 

advantage, NCI promotes collaborations that translate scientific understanding to the clinic. The 

largest such research activity supported by NCI is 

our Clinical Trials Program for testing cancer 

treatments, diagnostic tools, and interventions for 

preventing cancer and providing access as early as 

possible to all who can benefit. With the participation of more than 10,000 medical school and 

private practice physicians in NCI’s Clinical Trials 

Cooperative Group and Community Clinical 

Oncology programs, NCI supports over 1,300 

clinical trials a year involving more than 200,000 

patients.2 

In the early 1960s, we began one of our longest 

running partnerships by establishing the Cancer 

Centers Program. Congress encouraged the 

expansion of the Program to improve the quality 

Ongoing Research Shows Value of Centers of Research Excellence, 

Networks, and Consortia 

Specialized Programs of Research Excellence (SPOREs), other Centers of Research Excellence, and NCI-support networks and consortia provide opportunities for research that cannot be conducted by investigators at single institutions. 

■ Breast Cancer SPOREs are testing the use of imaging and gene array assessments to find markers that predict longterm response to chemotherapy before breast cancer surgery. These kinds of techniques may allow patients and their 

physicians to make more confident decisions to use the therapy as well as to help identify patients who are likely to 

relapse and may wish to consider other options. 

■ Ovarian Cancer SPOREs are participating in a screening trial to test the efficacy of obtaining periodic CA 125 values and 

to determine if this screening method, along with transvaginal ultrasounds, is effective for early detection in women at 

high risk for ovarian cancer. The trial is being conducted through collaboration with the Cancer Genetics Network. 

■ Prostate Cancer SPOREs have worked together to develop the necessary infrastructure to validate relevant biomarkers 

for prostate cancer using high throughput analysis and technologies that will ultimately bring into clinical practice new 

biomarkers for diagnosis, prognosis, and treatment. Additionally, the prostate SPOREs are developing microarrays for 

studies on special populations including African Americans, Hispanics, and Asian Americans. 

■ The Chronic Lymphocytic Leukemia (CLL) Research Consortium, a multi-institutional research program, brings 

together the nation’s top scientists from different disciplines to conduct an integrated program of basic and clinical 

research focused on a single disease. CLL is the most common, and currently incurable, adult leukemia. Nine 

institutions are engaged in six research projects. Five are laboratory based and the sixth is a multicenter program 

to conduct clinical trials of promising new agents. 

■ Two adult brain tumor consortia, the New Approaches to Brain Tumor Therapy CNS Consortium and the North 

American Brain Tumor Consortium, have greatly expanded the clinical research agenda for therapy in adults with 

gliomas and are considered the primary focus nationally for most new agent trials in adult brain tumors. These consortia 

have successfully evaluated the efficacy and pharmacokinetics of NCI-sponsored agents and incorporated molecular 

and biological analyses in clinical trials of novel agents aimed at specific molecular targets. Both consortia have 

established collaborations with industry sponsors. 

2 See pages 36-40 or more information about the NCI National Clinical Trials Program. 

A Plan and Budget Proposal for Fiscal Year 2004 15 OUR ROLE IN CANCER RESEARCH 
NCI Team Includes Advisory Groups 

Scientists, medical experts, and advocates work together to help shape NCI’s policies and programs 

through a number of standing and ad hoc advisory groups. The National Cancer Advisory Board provides 

overall guidance for NCI and a final assessment of the research proposals selected for funding through peer 

review. The Board of Scientific Counselors evaluates the progress, performance, and productivity of the 

Institute’s intramural research programs and scientists through regular site visits to NCI. The Board of 

Scientific Advisors plays a similar role for NCI’s extramural program, reviewing the progress of ongoing programs and providing feedback on proposed new research activities. NCI convenes Progress Review Groups 

of scientific and medical experts and advocates to examine the research needs and opportunities for specific types of cancer. NCI is also strongly influenced by the President’s Cancer Panel. This and other advisory 

groups provide seasoned assessment of progress and problems in the Nation’s effort to reduce the burden 

of cancer. 

In addition to their membership on other NCI advisory groups, advocates advise the NCI Director on broad 

program and research priorities through the Director’s Consumer Liaison Group. Members of this all-consumer advisory committee have provided assistance to the Institute in other ways as well, including gathering suggestions from the advocacy community on survivorship issues, disseminating and promoting cancer 

trials training, and assisting with various strategic planning efforts. NCI also solicits the advice of patients and 

their family members through the recently created Consumer Advocates in Research and Related Activities 

(CARRA) program. Through this program, approximately 200 individuals are available to participate in a wide 

range of NCI activities. For example, they participate in advisory groups to help assess needs for specific 

cancers, provide advice on the design of clinical trials, and review education materials. 

Go to deainfo.nci.nih.gov/advisory/boards.htm for more information on NCI Advisory groups. 

of cancer care by bringing cancer scientists and 

oncologists together in the same setting with 

patients and their families. Today, two-thirds of 

the 60 Centers funded by NCI are comprehensive 

Cancer Centers, so designated because of the 

breadth and depth of the research conducted by 

their investigators and their role in public education 

and outreach. 

NCI Centers of Excellence are smaller in scale 

than NCI Cancer Centers and generally focus on 

one or a few types of cancer or scientific areas. 

More than 40 Specialized Programs of Research 

Excellence bring together groups of cancer scientists with specialized expertise to focus on translational research for disease-specific cancers. NCI 

also brings investigators together for translational 

research through networks like the Early 

Detection Research Network, which assembles 

groups of scientists to identify markers and 

develop tests to detect early signs of cancer. 

Intervention Delivery and 

Communication 

While delivery of most interventions is ultimately 

the responsibility of healthcare and public health 

organizations, NCI’s role is to ensure that our 

research findings reach the community and are 

translated into practices that will make a difference 

in the lives of people. The results of NCI-supported 

research consistently provide cancer patients and 

those who care for them with information, tools, and 

tests that can be used for improved cancer interventions and can help people make better health 

choices and physicians select treatment options that 

are more targeted and less invasive and result in 

fewer adverse side effects. Evidence-based cancer 

control interventions influence the nature of public 

health programs to more effectively reduce cancer 

risk and promote better health practices. For example, once its effectiveness was confirmed in clinical 

trials, oncologists were quick to adopt the use of 

tamoxifen in the care of breast cancer patients. 

Likewise, since studies established the link between 

diet and cancer risk, more and more of us strive to 

include five servings of fruits and vegetables in our 

daily diets. 

NCI programs to reduce the disparities in the 

occurrence of cancer, its treatment, and outcomes 

among various racial and ethnic groups include 

research into the causes of health disparities and 

measures to translate research results into better 

health for groups at high risk for cancer. For 

example, NCI-supported investigators are using 

insurance data to examine the extent to which African 

American, Hispanic, and Caucasian patients are 

receiving recommended treatments for colon cancer. 

Researchers are also seeking the causes of disparities 

16 The Nation’s Investment in Cancer Research 
among other underserved groups. In addition, NCI 

is supporting field tests of smoking cessation and 

weight control programs targeted to the needs of 

specific racial and ethnic groups. 

NCI has partnered with other state and Federal 

agencies to work on a number of projects aimed 

at improving the quality of cancer care, such as 

efforts to raise the rates of colon cancer screening 

among veterans and the elderly and cervical cancer 

screening and treatment among lower income 

populations across the United States. 

When NCI-supported research results in discoveries 

that may lead to new drugs, novel technologies, 

or diagnostic tests, Federal laws encourage universities and NCI to pursue commercialization by 

licensing the discoveries to industry. In addition, 

NCI intramural investigators can also collaborate 

with industry through arrangements known as 

Cooperative Research and Development 

Agreements. It is through such an agreement 

between NCI and a major pharmaceutical company 

that investigators are following chronic myelogenous 

leukemia patients treated with the recently 

approved anti-cancer agent imatinib,3 to determine 

its long-term effects. 

While major scientific advances typically reach the 

medical community and the public through medical 

3 Also called STI571 or Gleevec.TM 

journals and news reports, NCI proactively disseminates information on new interventions through a 

range of other cancer communications activities. 

For example, NCI provides Web-based information 

on cancer and clinical trials, toll-free telephone 

service in all regions of the country, and printed 

brochures and educational packages distributed 

directly to consumers and through physicians and 

advocacy organizations. NCI-supported researchers 

work to create the best methods for reaching all 

who need to learn about cancer, with news of recent 

research findings and information on opportunities 

to participate in clinical trials. 

We also foster collaborations leading to new interventions through partnerships with other Federal 

and state agencies charged with strategic roles in 

improving the Nation’s health. For example, the 

preponderance of data on cancer trends have been 

collected and analyzed through the combined 

efforts of NCI, the Centers for Disease Control and 

Prevention, and state cancer registries. This information is critical to targeting public health interventions as well as informing our fundamental research 

hypotheses relating cancer susceptibility and environmental factors. Likewise, partnerships with the 

Food and Drug Administration and pharmaceutical 

companies are accelerating the pace with which we 

are able to move drugs through the pipeline of 

discovery, development, and delivery. 

Consortium Focuses on Developing Cancer Vaccines 

Recent advances in genomics and proteomics have enabled the discovery of novel molecular targets that 

appear well suited to a vaccine approach, and clinical trials have demonstrated that these vaccines can 

stimulate the immune system to attack cancer cells while eliminating or limiting toxicity. The approach has 

had efficacy in early trials in patients with advanced colorectal cancer, renal cell carcinoma, melanoma, and 

lymphoma. To speed the development of vaccines and their translation to patient care, NCI’s Center for 

Cancer Research has established a Vaccine Initiative to bring together a consortium of scientists with 

expertise in oncology, vaccinology, and translational research along with representatives of the biotechnology 

and pharmaceutical industries. Several vaccines developed by consortium members are currently being used 

in clinical care. 

Consortium researchers are also improving the effectiveness of new and existing vaccines by vaccinating with 

genetically engineered tumor cells to stimulate the immune system, adding genes to the vaccine mixture to 

produce proteins that are similar to or the same as the target on the cancer cell, and adding molecules to the 

vaccine mixture that are known to stimulate parts of the immune system. 

A Plan and Budget Proposal for Fiscal Year 2004 17 OUR ROLE IN CANCER RESEARCH 
People don’t get “cancer.” They develop cancer of the breast, the 

prostate, the lung, or any of over 100 other types of the disease. 

The recommendations of Progress Review Groups are central to 

sustaining the best possible science and making the fastest advances 

against specific cancers.— Andrew C. von Eschenbach, M.D. 

National Agendas for Disease-Specific 

Research 

Unlike the common belief of 30 or 40 years ago, we know today that there are more than 100 distinct types of cancer. We are also learning that many diseases have subtypes with unique molecular characteristics that influence how they develop and progress and how they can be effectively prevented, 

detected, and treated. For these reasons, NCI carries out an ambitious program of research on specific 

types of cancer. These efforts along with the broad-based programs described in this document provide 

the framework for national agendas for disease-specific research. 

NCI leads the development and pursuit of diseasespecific research by assessing the current understanding of specific cancers, the funded research, 

our ability to prevent and treat the disease, and the 

extent of our success. We chart the course primarily 

through advice from expert Progress Review 

Groups (PRGs) who work with us to evaluate the 

state of the science for specific types of cancer or 

groups of related cancers, identify research gaps and 

resource needs, and develop recommendations for 

future priorities. NCI’s planning and evaluation 

process for disease-specific research involves three 

distinct phases: developing recommendations 

through the PRGs, planning for and implementing 

those recommendations with advice from internal 

implementation working groups, and reporting on 

progress. This comprehensive and integrated 

approach to planning helps us demonstrate our 

progress and the wise use of resources to the scientific community and the public. Through these and 

other crosscutting efforts, NCI establishes a framework for accountability that is in keeping with the 

President’s Management Agenda and the 

Congressionally mandated Government 

Performance and Results Act. 

Developing Recommendations 

Progress Review Groups (PRGs) are panels of 20 

to 30 prominent members of the scientific, medical, 

private sector, and advocacy communities who are 

selected to assess the state of the science and 

recommend future research-related priorities for 

one type of cancer or a group of closely related cancers. The deliberations of each PRG are informed 

by a larger group of more than 100 leaders from 

diverse disciplines and the advocacy community 

who assemble for a Roundtable Meeting to discuss 

their understanding of the disease, barriers to 

progress, and key research and resource priorities 

for the next five years. PRGs use the input from 

these Roundtable groups to develop comprehensive 

and widely distributed reports and recommendations for national research agendas.1 

For example, recently assembled PRGs have identified some specific initiatives they believe are needed to speed research progress. 

■ The Gynecologic Cancers PRG has identified 

a need to develop a virtual shared specimen 

resource that will improve timely access to high 

quality tissue and body fluid samples and enable 

gynecologic cancer researchers to exploit emerging genomics, proteomics, and informatics technologies. This critical tool would support the discovery of new and urgently needed early detection methods and new prevention and treatment 

targets. 

■	 The Lung Cancer PRG believes faster progress 

against the difficult problem of lung cancer will 

be achieved with scientifically integrated, interdisciplinary, multi-institutional consortia organized 

18 

1 prg.cancer.gov 

The Nation’s Investment in Cancer Research 
around the disease, rather than around scientific 

disciplines. Among its other top recommendations, this PRG has underscored the need for 

continued research on the genetic, social, and 

biobehavioral aspects of tobacco control and the 

need to better elucidate the contributions of 

injury, inflammation, and infection on lung 

cancer development. 

■	 The Kidney and Bladder Cancers PRG has 

identified and prioritized research questions 

across the full spectrum of fundamental research, 

intervention development, and delivery that will 

advance progress against these cancers over the 

next five years. One priority area identified by 

this group focuses attention on our need to better 

understand the tumor microenvironment, which 

likely plays an important role in tumor development and growth in bladder and kidney cancers. 

Most studies to date have examined only the 

characteristics of the cancer cells. Expanding the 

scope of research to include analysis of interactions between the cancer cell and its immediate 

surroundings and cancer-associated changes in the 

tumor microenvironment will help researchers to 

understand the role of cellular communication in 

tumor development and maintenance. This recommendation aligns with NCI’s new thrust to 

explore how the interaction between the cancer 

cell and its microenvironment enables and even 

promotes tumor growth.2 

A number of common themes have emerged across 

PRG recommendations that parallel priority initiatives identified in this document. For example, the 

following were emphasized in more than one PRG 

recommendation and are closely tied to the capacity 

building initiatives described on pages 26-45 for 

supporting research collaborations or development 

of and access to research resources. 

■	 Cross-disciplinary collaborations such as additional Specialized Programs of Research 

Excellence (SPOREs) and consortia focused 

on disease-specific research 

2 See pages 55-59 for NCI’s future plans for research on the tumor microenvironment. 

Planning National Agendas for Disease-Specific Research: 

The Progress Review Group (PRG) Process 

Recommendation 

■	 NCI leadership appoints 

PRG co-chairs. 

■	 PRG co-chairs identify & 

invite PRG members. 

■	 PRG members plan roundtable. 

■	 Roundtable meets & 

develops recommendations. 

■	 PRG members 

prepare report & 

recommendations. 

Implementation 

■	 NCI establishes Working 

Group of internal experts. 

■	 NCI maps its initiatives & 

projects to PRG 

recommendations. 

■	 NCI prepares 

proposed response to 

recommendations. 

■	 NCI and PRG hold response 

meeting. 

■	 NCI prepares & promotes 

disease-specific strategic 

plan. 

Reporting 

■ NCI collects progress data. 

■ NCI develops a progress 

report. 

■ NCI & PRG discuss 

progress. 

In the reporting phase: 

Breast Cancer 

Prostate Cancer 

19 N A TIONAL AGENDAS FOR DISEASE-SPECIFIC RESEARCH 

Status of the Process for Established PRGs as of September 2002 

In the recommendation phase: In the implementation phase: 

Stomach & Esophageal Cancers Colorectal Cancers


Brain Tumors


Pancreatic Cancer


Leukemia, Lymphoma, & 


Myeloma


Lung Cancer


Gynecologic Cancers


Kidney & Bladder Cancers


A Plan and Budget Proposal for Fiscal Year 2004 

■	 PRG co-chairs present recommendations to Advisory 

Committee to the Director. 

■	 NCI revises & promotes 

disease-specific strategic 

plan. 
■	 Enhanced bioinformatics to enable better 

researcher access to data and analytic tools 

■	 Training on emerging technical developments 

and career development opportunities related to 

specific types of cancer, to attract new 

investigators 

■	 More extensive and fully documented tissue 

resources 

■	 Preclinical models that more faithfully reflect 

the behavior of specific tumors in humans 

Other recommendations may be addressed through 

our priority initiatives described on pages 48-92 for 

supporting research on genes and the environment, 

signatures of the cancer cell and its microenvironment, molecular targets, cancer imaging, survivorship, and cancer communications. 

■	 Discovery of genetic and environmental factors 

and interactions that lead to cancer 

■	 Definition of molecular pathways and cellular 

interactions involved in cancer initiation, 

progression, and metastasis 

■	 Molecular profiling for the detection of 

precancerous conditions and early cancers and 

for monitoring treatment response 

■	 Development and testing of molecular targeted 

therapy 

■	 Improved imaging for early detection, guided 

therapy, and real time monitoring of treatment 

response 

■	 Treatment side effect and quality of life outcomes studies, including establishing registries 

and cohorts for study 

■	 Education of medical providers and patients 

about cancer risk, prevention, detection, 

treatment, follow-up, and end-of-life care 

20 

NCI Programs Support Disease-Specific Research 

A number of NCI’s existing programs support research focused on specific types of cancer. 

■	 Specialized Programs of Research Excellence (SPOREs) have proven to be highly effective channels for disease-specific translational research. The scope of the SPOREs is expanding to establish 

research hubs for additional cancers so that by the end of Fiscal Year 2002, 40 disease-specific 

SPOREs will be supported, with further expansions planned. Much of this expansion has been in 

response to PRG recommendations. Increasingly, SPOREs are partnering with Cancer Centers and 

NCI-sponsored research networks and consortia to build synergism and share resources to speed 

progress against specific cancers. Current SPOREs exist for brain, breast, gastrointestinal, 

genitourinary, head and neck, lung, ovarian, pancreatic, prostate, and skin cancer sites as well as 

for lymphoma. Future SPOREs will be established for gynecological, leukemia, and myeloma cancers. (See pages 8, 10, 11, and 30 to learn about specific research activities taking place at 

SPOREs).3 

■	 Early Detection Research Network (EDRN) participants develop, evaluate, and validate markers for 

earlier cancer detection and risk assessment. The Network includes academic and private collaborations and resources for basic, translational, and clinical research. EDRN collaborative groups 

include those focused on breast, gynecologic, gastrointestinal, lung and upper aerodigestive tract, 

prostate, and urologic cancers.4 

■	 NCI’s Innovative Molecular Analysis Technologies (IMAT) program focuses on developing and 

applying technologies that identify the expression of genes and gene products, the function of 

major cellular communication pathways involved in cancer, the role of infectious agents in specific 

cancers, and the significance of other molecular alterations that distinguish normal cells from 

cancerous ones. (See page 58 for additional information).5 

■	 The Mouse Models of Human Cancers Consortium (MMHCC) develops new preclinical models that 

will enable investigators to better understand specific human cancers and predict the effects of 

promising therapies. New models continue to be developed for sarcomas and for lung, prostate, 

mammary, skin, cervical, ovarian, nervous system, blood system, and gastrointestinal cancers. The 

MMHCC fosters collaboration in these efforts with industry partners and other research institutions.6 

3 spores.nci.nih.gov 

4 cancer.gov/prevention/cbrg/edrn 5 otir.nci.nih.gov/tech/imat 6 emice.nci.nih.gov 

The Nation’s Investment in Cancer Research 
21 NA TIONAL AGENDAS FOR DISEASE-SPECFIC RESEARCH 

Implementing Strategies to 

Address PRG Recommendations 

Formal strategic plans that respond to PRG 

recommendations are now being developed under 

the leadership of disease-specific working groups 

at NCI. The Brain Tumor Working Group 

proposed the application of new concepts 

in developmental neurosciences to understand the 

unique organ-specific biological mechanisms of 

gliomas in both pediatric and adult patients. The 

Leukemia, Lymphoma, and Myeloma Working 

Group suggested convening a meeting of leaders 

from academia, industry, the advocacy community, 

and government to examine models for establishing 

public-private partnerships for drug discovery. This 

could lead to a concept for the funding of planning 

grants and eventually drug development centers. 

The Pancreatic Cancer Working Group encouraged the funding and training of new investigators, 

imperative in advancing research on pancreatic cancer. 

NCI does everything in its power to expedite 

progress against all types of cancer. We implement 

as many of the proposed initiatives in the diseasespecific strategic plans as possible, and encourage 

and enable other organizations to take leading 

roles on those initiatives where additional collaboration is needed. PRG recommendations are implemented through ongoing NCI initiatives, new 

or expanded research programs, infrastructure 

support, partnerships, or a combination of these 

approaches. Our ability to implement any new 

initiative is dependent on (1) determining that the 

initiative is vital, feasible, and sound, (2) availability 

of funds, and (3) receipt of high quality applications or proposals. 

A Plan and Budget Proposal for Fiscal Year 2004 

Stalking a Silent Killer — Pancreatic Cancer 

Pancreatic cancer is often called a “silent” cancer because it has no clear symptoms until it is advanced. 

This malignancy metastasizes early, with many tumors as small as 1 or 2 centimeters in diameter spreading 

beyond the pancreas, and it is resistant to both chemotherapy and radiation treatment. Most patients live 

six months or less after diagnosis. In 2002, approximately 30,300 new cases will be diagnosed. Experts 

estimate that 29,700 people will die from this disease in the same time period. Finding better ways to 

detect, diagnose, and treat pancreatic cancer is absolutely critical. 

Researchers are pursuing a number of avenues in search of answers about pancreatic cancer: 

■ Old age, cigarette smoking, genetic history, chronic pancreatitis, and diabetes are established risk 

factors for pancreatic cancer. A recent study indicates that obesity increases susceptibility. People who 

have first degree relatives who have had the disease have a threefold higher risk compared with the 

general population. Researchers are now trying to learn more about other suspected and corollary 

risk factors such as chemical exposures and diet in hope of developing effective preventive measures. 

■ One important avenue of research is to find genes or gene products that influence the tumor’s development or progression and could serve as early detection or diagnostic indicators, or targets for better 

therapies. Research is uncovering a growing number of such genes. 

■ Several hereditary syndromes and their related genes (such as p16, BRCA2,7 STK11/LKB1, hMSH2, 

hMLH1, PRSS1) have been identified, but these probably account for no more than 5-10 percent of 

cases. 

■ Known non-hereditary genetic alterations include activation of the K-ras cancer gene, inactivation of a 

number of tumor suppressing and DNA repair genes, and overexpression of several growth factors and 

receptors. 

■ Researchers in the United States and abroad are looking for genes that are influenced by environmental 

exposures. For example, a recent NCI-funded study demonstrated that a specific deletion in the GSTT1 

gene combined with heavy smoking increased pancreatic cancer risk significantly among Caucasian 

study participants, with the effect greater in women than in men. 

NCI’s Pancreatic Cancer Progress Review Group emphasized in its 2001 report8 that insufficient research 

funding and the limited number of researchers dedicated to studying the disease have hampered progress 

against this silent killer. NCI is taking specific steps to help increase the level of research on this highly 

fatal disease and to encourage researchers to commit to improving care for patients and those at risk for 

pancreatic cancer. 

7 See page 10 for more information. 

8 prg.cancer.gov/pancreatic/finalreport 
Reporting on Progress 

We close our accountability feedback loop by providing details to the community on actions we have 

taken to address PRG recommendations. 

Recognizing that some actions take longer to 

demonstrate results, NCI monitors implementation 

and collects progress data for several years and then 

prepares a progress report. This report is shared with 

a reassembled PRG. Based on NCI’s assessment of 

progress and PRG input, implementation strategies 

are revised, retired, or added as needed, and NCI 

continues to monitor progress. 

By 2003 we will publish progress reports for prostate 

cancer and breast cancer, in follow-on to the first two 

PRG reports issued in 1998. NCI will also complete 

an evaluation of the PRG process itself before the 

end of this year. The chart on page 19 indicates the 

current status of reports and plans related to the 

PRGs established to date. 

How We Measure Progress 

■	 Disease trends: decreased incidence, 

earlier stage of diagnosis, longer survival 

time, improved quality of life, lower 

mortality rate 

■	 New FDA-approved interventions: new 

prevention & treatment agents & drugs, 

improved diagnostic & treatment 

technologies 

■ Ongoing & new clinical trials 

■	 Advances in scientific knowledge: reports 

of research findings, peer-reviewed 

publications 

■ NCI-supported research projects 

22 The Nation’s Investment in Cancer Research 

Targeting a Tumor on the Rise — Kidney Cancer 

The incidence of kidney cancer has been increasing about two percent per year for the past several decades. 

For African Americans, it is rising more rapidly than any other cancer — about four percent per year. Kidney 

cancer, including tumors of the main part of the kidney and the lower renal pelvis, is now diagnosed in nearly 

32,000 people each year in the United States. About 200,000 people are living with kidney cancer. Mortality 

from the disease is also high and rising, with an estimated 11,600 deaths expected in 2002. 

Four main types of kidney cancer have been identified. Clear cell renal tumors are the most common type, 

accounting for about 75 percent of cases. The reasons for the increase in incidence are not fully understood. 

Smoking is the most well established risk factor. Obesity, hypertension, occupational exposures, and heavy, 

long-term use of the pain medication phenacetin have also been linked to greater risk. A small percentage 

of kidney cancers are hereditary. 

More than 40 percent of kidney cancers are not diagnosed until advanced stages. Five-year survival of 

patients who present with advanced kidney cancer is nine percent. By contrast, approximately 90 percent 

of patients diagnosed with Stage I disease survive at least five years. Scientists are actively exploring the 

growing field of proteomics to identify growth factors and other circulating proteins that may be indicators 

of disease and that can serve as biomarkers for early detection. 

Currently, for localized kidney cancer, surgery is the only effective treatment. Minimally invasive and kidneysparing surgical techniques are becoming more widely used. For metastatic kidney cancer, Interleukin-2 (IL-2) 

is the only approved treatment. Though highly toxic, IL-2 cures about 10 percent of patients. Scientists are 

investigating several important molecular pathways as potential targets for less toxic treatments. For example, 

anti-angiogenesis agents may prove beneficial against clear cell renal tumors. In a recent Phase II clinical trial, 

high doses of the antibody bevacizumab slowed tumor growth considerably in patients with metastatic kidney 

cancer. 

9 More than 20 other trials are now underway to evaluate this antibody as a treatment for other types 

of cancer. 

In 2001, NCI convened a Kidney and Bladder Cancers Progress Review Group to assess our understanding 

and treatment of these diseases and identify research priorities and infrastructure needs for accelerating 

progress over the next 5 to 10 years. An NCI implementation planning group has been convened to analyze 

the recommendations10 and determine how the recommendations can be implemented. 

9 See page 10 for more information. 

10 prg.cancer.gov/kidney 
PEOPLE’S STOR Y 

A Plan and Budget Proposal for Fiscal Year 2004 23

Esophageal Cancer 

People’s Story 

A couple of years ago, I started having 

frequent indigestion and heartburn. 

I’ve always loved spicy food, and 

I figured, at my age, my stomach was 

finally starting to complain about it. 

But I was taking more and more 

antacids, so I finally mentioned 

it to my doctor. After talking to him, 

I was glad I did. 

This year, more than 13,000 people will be diagnosed with esophageal cancer and an estimated 12,600 will 

die of this disease. It will strike three to five times more men than women. Of the two types of esophageal 

cancer, squamous cell tumors have been historically more prevalent. However, for reasons that are not 

well understood, rates of adenocarcinomas of the esophagus are rising at an alarming rate. 

The rise in adenocarcinoma has 

been extraordinarily steep among 

white men, surpassing the incidence of squamous cell tumors 

in this population. 

In contrast, African American 

men, who have the highest overall esophageal cancer rates of any 

population in the United States, 

develop squamous cell tumors 

more often than adenocarcinomas. Moreover, they tend to 

develop the disease earlier than 

other groups and have poorer survival rates. Though still high, 

squamous cell esophageal cancer 

rates are falling among African 

American men, possibly due to 

lower smoking rates since the 1960s. 

Barrett’s esophagus is the most 

significant precursor for 

esophageal adenocarcinoma. 

It occurs when normal squamous 

epithelial cells that line the lower 

esophagus are replaced by columnar epithelial cells such as those 

normally found in the stomach. 

The condition is believed to be 

linked to the chronic reflux 

(backing up) of stomach acid into 

the esophagus, and obesity has 

been shown to increase the risk. 

Many cases of Barrett’s esophagus 

are preventable since the condition is easy to detect with a relatively simple test. But patients 

may consider even chronic heartburn too trivial to mention to 

their doctors, and often physicians 

fail to ask about the problem. 

The most effective screening and 

treatment approaches for Barrett’s 

esophagus remain in question. 

Studies suggest that a few risk factors account for virtually all of the 

squamous cell esophageal cancers 

in the men studied and for 99 

percent of the excess occurence 

in African American men. 

■ Major contributors to the 

development of squamous 

cell esophageal cancer are 

tobacco use and heavy alcohol 

consumption, particularly in 

combination. 

■ A recent NCI study reports 

that low income and infrequent consumption of fruits 

and vegetables also account for 

susceptibility to this disease. 

For all esophageal cancers together, 

the median age at diagnosis for 

males is 67 years. For females, it 

is 73 years. Of these, 66 percent 

will be in the age group 65 years 

and older. 

In 2002, NCI convened a 

Stomach and Esophageal Cancer 

Progress Review Group to assess 

the current state of knowledge 

about esophageal cancers and 

identify the research and 

resources needed to answer the 

many important questions about 

both forms of this deadly disease. 

Go to prg.cancer.gov/stomach 

to see the report. 
Planning and Priority Setting for 

Cancer Research 

NCI plans and sets priorities to ensure that we are responsive to new discoveries and opportunities, while making the best use of our resources. NCI staff work together and with public and private 

partners from the scientific, medical, and advocacy communities to determine what is needed and how 

best to move the science forward. We plan for research that can address critical unanswered questions 

covering the many types of cancer and the various populations that experience them. We strive to integrate basic, behavioral, population, and applied research through translational activities and strive to 

identify new opportunities, as well as gaps and barriers to progress, that help us create new programs 

and improve existing ones. We keep our research portfolio balanced and our support structure strong 

through program assessment. 

Over the past several years, the National Cancer 

Institute has identified and fostered the development 

of several broad priority areas that serve as the framework for our annual strategic planning and budget 

development. NCI Challenges are areas of emphasis that focus investment on improving the resources 

and mechanisms available to support research, furthering the preparation of the people needed to conduct research, enhancing access to research information and technology, and maximizing the sharing of 

discovery and collaboration among researchers and 

clinicians. Extraordinary Opportunities for 

Investment are areas of discovery that build upon 

the most important recent developments in knowledge and technology and hold promise for making 

significant progress against all cancers. They are 

developed with formal input from members of the 

research community, advisory groups, and advocacy 

organizations. These priority areas are the “breaking 

news,” the emergent fields of cancer research. Some 

of these Challenge and Extraordinary Opportunity 

areas also address major public health needs or concerns that have potential to affect large numbers of 

people at risk for or affected by cancer. Pursuing 

these priorities will enhance our understanding of the 

clinical outcomes resulting from cancer interventions; 

improve our ability to apply the best available cancerrelated knowledge, technology, and interventions in 

clinical practice and public health; and ensure that we 

do all that we can to reduce health disparities in cancer incidence and outcomes. 

Thus, the framework for our Fiscal Year 2004 Plan 

and Budget is comprised of three major components 

to complement our core budget for continuing 

research and support activities. Each of these includes 

cross-cutting and focused research on specific types 

of cancer as described in the National Agendas 

for Disease-Specific Research developed in 

consultation with Progress Review Groups. 

■ Building the Nation’s Cancer Research 

Capacity requires increased support to four 

NCI Challenge areas: 

— Enhancing Investigator-Initiated Research 

— Expanding the Capacity of Centers 

Networks, and Consortia 

— National Clinical Trials Program in 

Treatment and Prevention 

— Developing Bioinformatics for Cancer Research. 

■	 Advancing Discovery and Its Application 

means further pursuing “Extraordinary 

Opportunities for Investment” in: 

— Genes and the Environment 

— Signatures of the Cancer Cell and Its 

Microenvironment 

— Molecular Targets for Prevention and 

Treatment 

— Cancer Imaging and Molecular Sensing 

— Cancer Communications 

■	 Addressing Areas of Public Health Emphasis 

requires increased support for: 

— The Challenge for Improving the Quality of 

Cancer Care 

— The Challenge for Reducing Cancer-Related 

Health Disparities 

— A new Extraordinary Opportunity in 

Cancer Survivorship research 

— An Extraordinary Opportunity for Research 

on Tobacco and Tobacco-Related Cancers 

A Plan and Budget Proposal for Fiscal Year 2004 

PLANNING AND PRIORITY SETTING FOR CANCER RESEARCH 
The Nation’s Investment in Cancer Research 

Distribution of 2004 Budget Request ($5,986,000,000) 

Distribution of 2004 Requested Increases ($1,348,131,000) 

Research Project Grants 45.5% 

Other Grants 1.5% 

Research Management and Support 4.0% 

Research Support Contracts 11.2% 

Cancer Control Operations 3.3% 

Training and Education Grants 3.1% 

Intramural Research 4.3% 

Cancer Centers 8.0% 

SPOREs 5.0% 

Clinical Trials 

Infrastructure 17.3% 

Training and Education 

Grants 1.2% 

Cancer Control 

Operations 0.6% 

Clinical Trials Infrastructure 9.3% 

SPOREs 3.3% 

Cancer Centers 6.1% 

Intramural Research 12.8% 

Other Grants 2.0% 

Research Management 

and Support 5.0% 

Research Support Contracts 15.8% 

Research Project Grants 40.9% 

Research Project Grants 

Funding for extramural research, primarily 

through investigator-initiated Research 

Project Grants (RPGs), comprises the 

largest part of the NCI core budget. 

Increases through the NCI Challenge and 

Extraordinary Opportunity initiatives contribute to the expansion of research supported through RPGs. NCI funds about 

4,500 RPGs each year to nearly 600 institutions across the United States at an average 

cost of approximately $400,000 per grant. 

If fully supported, our budget request for 

Fiscal Year 2004 would add $523 million to 

the funds available to support investigatorinitiated research. 

Intramural Research 

NCI intramural research focuses on 

projects conducted by some 400 

researchers located on the NIH campus. These researchers build upon the 

proximity between their research laboratories and the NIH Clinical Center 

and the synergism among NIH 

Institutes to support the rapid translation of basic laboratory research to the 

clinic and to maintain a special focus on 

long-term epidemiologic and genetics 

studies. 

Cancer Centers and Special 

Programs of Research Excellence 

(SPOREs) 

Sixty NCI-supported Cancer Centers 

serve as hubs for cutting-edge research, 

high quality cancer care, and outreach 

and education for healthcare providers 

and patients. Centers of Excellence like 

the SPOREs use flexible funding to pursue questions related to specific forms of 

cancer and to move disease-specific 

research quickly from the laboratory to 

the patient. Funding increases will allow 

NCI to broaden the number and range of 

activities at Cancer Centers and SPOREs. 
NCI Budget Request for 2004


2002 2003 2004 Budget Request 

Operating President's 

(dollars in thousands) Budget Budget Increases Total 

Research Project Grants (RPGs) 

Ongoing $1,450,697 $1,557,941 $ 89,160 $1,647,101 

New and Renewal 456,000 516,711 434,625 951,336 

Subtotal 1,906,697 2,074,652 523,785 2,598,436 

Small Business Innovation Research 85,995 100,294 26,995 127,289 

Total RPGs 1,992,692 2,174,946 550,779 2,725,725 

Intramural Research 630,036 706,258 58,132 764,390 

Cancer Centers 227,831 254,246 107,937 362,183 

Specialized Programs of Research Excellence (SPOREs) 108,921 127,696 67,725 195,420 

Clinical Trials Infrastructure 

Cooperative Clinical Research 161,711 198,060 157,628 355,688 

Community Clinical Oncology Program (CCOPs) 105,522 123,187 76,108 199,295 

Total Clinical Trials Infrastructure 267,233 321,247 233,736 554,983 

Training and Education Grants 

National Research Service Awards 64,083 73,289 4,926 78,215 

Research Career Program 54,177 65,327 5,500 70,827 

Cancer Education Program 27,170 25,456 3,942 29,398 

Minority Biomedical Research Support 3,980 4,522 1,167 5,689 

Total Training and Education Grants 149,410 168,594 15,535 184,129 

Cancer Control Operations 154,306 188,429 7,722 196,151 

Research Support Contracts 425,440 457,941 212,644 670,585 

Research Management and Support 150,757 173,200 66,758 239,958 

Other Grants 60,371 65,313 27,163 92,475 

Total NCI 4,166,997 4,637,869 1,348,131 5,986,000 

Cancer Control included above** 491,645 546,792 308,821 855,613 

Clinical Trials Infrastructure Training and Education Grants Cancer Control** 

NCI supports clinical trials carried out by NCI funds approximately 170 institu- NCI’s cancer control operational funds 

approximately 10,000 investigators at tions and 2,000 individuals each year along with numerous grants and contracts 

some 1,700 U.S. hospitals and Cancer through extramural cancer research included throughout the budget are used 

Centers each year. Nearly 1,500 trials are training programs to prepare the next to support research, communication, and 

conducted annually, assisting over generation of scientists and clinicians to other activities focused on ways to reduce 

200,000 patients. These trials make possi- use new technologies and work effec- cancer risk, incidence, morbidity, and morble the testing of targeted agents that tively in interdisciplinary, collaborative tality and improve the quality of life for all 

hold promise for more effective, less inva- research environments. Increased cancer patients. Increases will be used to 

sive, cancer prevention and treatment and funding will be used to enhance these support research on tobacco and tobaccotechnologies that can be used for better programs and to support the participa- related cancers, reducing cancer-related 

detection and diagnosis. About three- tion and growth of scientists within health disparities, improving the quality of 

quarters of this funding is for treatment underserved populations. cancer care, cancer survivorship, cancer 

trials and the other quarter supports pre- communications, and a host of other inforvention and screening trials. mation dissemination activities. 

24 The Nation’s Investment in Cancer Research 
Requested Increases for Fiscal Year 2004* 

Discovery and Public Health 

Capacity Building Application Emphasis Total 

(dollars in thousands) Core Increase Increase Increase Increase Increases 

Research Project Grants (RPGs) 

Ongoing $ 89,160 $ - $ - $ - $ 89,160 

New and Renewal 35,988 99,737 169,100 129,800 434,625 

Subtotal 125,148 99,737 169,100 129,800 523,785 

Small Business Innovation Research 20,995 - 6,000 - 26,995 

Total RPGs 146,142 99,737 175,100 129,800 550,779 

Intramural Research 26,132 27,000 5,000 - 58,132 

Cancer Centers 24,907 72,830 8,200 2,000 107,937 

Specialized Programs of Research 

Excellence (SPOREs) 32,725 30,500 4,500 - 67,725 

Clinical Trials Infrastructure 

Cooperative Clinical Research 7,328 132,900 7,500 9,900 157,628 

Community Clinical Oncology 

Program (CCOPs) 4,558 71,550 - - 76,108 

Subtotal 11,886 204,450 7,500 9,900 233,736 

Training and Education Grants 

National Research Service Awards 4,926 - - - 4,926 

Research Career Program 2,500 - - 3,000 5,500 

Cancer Education Program 942 - 1,000 2,000 3,942 

Minority Biomedical Research Support 1,167 - - - 1,167 

Subtotal 9,535 

Cancer Control Operations 6,972 

Research Support Contracts 16,944 

Research Management and Support 6,408 

Other Grants 12,363 

- 1,000 5,000 15,535 

- - 750 7,722 

103,850 44,450 47,400 212,644 

39,150 16,700 4,500 66,758 

- 3,800 11,000 27,163 

Total NCI 294,014 577,517 266,250 210,350 1,348,131 

*Increases over the 2003 President’s Budget 

Research Support Contracts Research Management and Other Grants 

Research support contracts are used Support Other grants support partnerships and 

to support program efforts across the Research management and support shared resources and scientific evaluaInstitute. Areas that utilize contracts budgets are used for the critical techni- tion, workshops and conferences. 

are diverse and include such areas as cal and administrative services required 

drug development, cancer control for NCI to carry out its work. They 

research, information dissemination, include central administrative funcand support to epidemiological tions, overall program direction, grant 

research. and contract review and administration, 

personnel, program coordination, and 

financial management. 

25NCI BUDGET REQUEST 

A Plan and Budget Proposal for Fiscal Year 2004 
The ever-changing technological and scientific landscape requires that we constantly re-examine how 

we interact as scientists to conduct our research 

and what resources are necessary to yield results. 

— Andrew C. von Eschenbach, M.D. 

Building the Nation’s Cancer 

Research Capacity 

The challenge before NCI is to build and continually enhance a research system that will allow and 

encourage the scientific community to share and apply new discoveries and emerging technologies. We 

need new funding arrangements that will promote and reward innovative thinking; speed cross fertilization of ideas among disparate scientific disciplines; facilitate collaborations among government, academia, and industry; and bring advances in cancer care to all populations. And we need to foster and coordinate efforts that would be too large for the individual investigator by promoting team endeavors, and by 

encouraging scientific integration without inhibiting individual creativity. 

Advances in working with specific types of cancer 

may emerge from non-specific cancer knowledge 

and resources, and new knowledge in one type of 

cancer often has implications for better understanding other cancers. To make progress for as many 

cancers as possible, we need to: 

■	 Guide, support, leverage, and build the work of the 

individual investigator along with that of our NCIsupported Cancer Centers, networks, and consortia. 

■	 Maximize caregiver and patient access to clinical 

trials for prevention, diagnostic, and therapeutic 

interventions. 

■ Train top researchers in oncology and arm them 

with the finest technologies and tools available. 

■ Build and sustain the interdisciplinary 

connections so vital to 21st century science. 

We will continue to build the Nation’s cancer 

research capacity for the future by Enhancing 

Investigator-Initiated Research, Expanding the Capacity 

of Centers, Networks, and Consortia, maximizing the 

impact of our National Clinical Trials Program in 

Treatment and Prevention, and Developing 

Bioinformatics for Cancer Research. 

FY 2004 Increase Request for Capacity Building 

(dollars in thousands) 

Investigator-Initiated Research $ 69,887 

Centers, Networks, & Consortia $ 79,530 

National Clinical Trials Program $340,100 

Bioinformatics $ 88,000 

Total $577,517 

National Clinical Trials 

Program 49.3% 

InvestigatorInitiated 

Research 

12% 

National Clinical Trials 

Program 

59% 

Centers, Networks, 

& Consortia 

14% 

Bioinformatics 

15% 

26 The Nation’s Investment in Cancer Research 
NCI Challenge: Building Our Capacity for the Future 

Enhancing Investigator-Initiated Research 

GOAL 

Accelerate discoveries 

and their application by 

expanding and facilitating researcher access 

to resources and new 

technologies. 

The Challenge 

Investigator-initiated research — research independently conceived and developed by scientists — 

has always been the primary means by which biomedical research is funded and conducted. Driven 

by the synergism at medical schools, hospitals, universities, and research centers, these investigators 

ask the critical questions, explore the options, 

develop and test innovative technology, and make 

the discoveries that lead to better cancer science 

and its application. Investigator-initiated research is 

also the principal means by which NCI supports 

efforts to address high-priority goals, such as those 

identified by the Progress Review Groups. 

Recent advances, highlighted by the completed 

sequencing of the human genome, new technologies for identifying molecular targets within cancer 

cells, and methods for discovering and analyzing 

promising drugs aimed at each cancer-causing pathway, have outfitted scientists with a wider arsenal of 

approaches and technologies for research than ever 

before. The exploration of what we can learn from 

analyzing all of the genes altered in a cancer cell is 

expanding rapidly. Even as this is happening, investigators are developing powerful methods to analyze 

the vastly more complex array of proteins made in 

the cell. This offers a more direct route to identify 

targets for new drugs. However, to take advantage of 

these advances, researchers often require additional 

resources, in the form of new research tools and 

equipment, collaborators from different disciplines, 

or special support for translational research. 

Providing these resources is part of NCI’s challenge 

in the area of investigator-initiated research. 

NCI has seen an enormous increase in the need 

for funding to allow scientists to fully exploit 

new technologies and approaches to conducting 

research. In Fiscal Year 2002, for example, the 

number of applications submitted to NCI increased 

by 6 percent, and the cost of research projects supported by NCI was nearly 14 percent higher than 

the year before. This cost increase reflects a larger 

number of total active awards as well as modest 

growth in average cost. While we expect this trend 

to moderate, we must balance the growing number 

of research opportunities with the rising costs of 

research. Though reviewer assessments of research 

applications consistently identify the top 35 to 40 

percent of grants as highly meritorious, the proportion actually funded (the success rate) has averaged 

29 percent in recent years. NCI has maintained this 

success rate by carefully reviewing individually 

approved grant applications for programmatic 

changes, the effect of which is, on average, a reduction of 10 percent to the cost of a grant. As research 

opportunities increase, we must, in addition to 

leveraging our Federal dollars, ask researchers to 

complement this funding from other sources as 

much as possible. 

The next generation must choose to enter cancer 

research because of opportunities for discovery 

with the potential to change our world. A sufficient 

infusion of resources and funding into investigatorinitiated research will help to ensure that students 

considering a career in science, as well as current 

researchers, will perceive cancer research as an 

appealing and rewarding profession. 

Progress Toward 

Meeting the Challenge 

The NCI has sought to support and foster investigator-initiated research through a variety of policy 

decisions and flexible funding options. 

27 BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

A Plan and Budget Proposal for Fiscal Year 2004 
The Plan 

Enhancing Investigator-Initiated Research 

GOAL 

Accelerate discoveries and their application by expanding and facilitating researcher 

access to resources and new technologies. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Accelerate the pace of discovery through increased funding for and 

greater numbers of competing research grants. 

■ Support research projects to move toward funding at the full levels recommended by 

peer reviewers. 

■ Fund, at a minimum, 35 percent of competing applications — those with (1) the 

highest scientific merit, (2) a less certain probability of success but potential to yield 

greater reward if they do succeed, (3) unconventional approaches but unique 

promise, (4) a focus on areas of extraordinary need in specific fields of investigation 

or model systems, and/or (5) the involvement of new investigators. 

2. Encourage investigators to commit to careers in cancer research 

and to propose more innovative and higher reward projects. 

■ Continue to allocate the first 80 to 90 percent of available funds for research project 

grants through the well-established peer review selection process while ensuring that 

proposals from new investigators are also funded at a rate comparable to those of 

more established investigators, utilizing exceptions as necessary. 

■ Through a special administrative evaluation process, fund particularly innovative and 

potentially high reward projects. 

3. Facilitate rapid movement from discovery to application by using 

established mechanisms and creating novel special awards to 

encourage transdisciplinary and collaborative research. 

■ Expand supplemental funding for grants that promote new interdisciplinary collaborations for bringing together basic, clinical, and population scientists, such as those 

28 

Balancing Investigator-Initiated Research Projects and Large Initiatives 

There’s no substitute for individual insight and creativity. That’s why the traditional research project grant 

(R01) remains the heart of the NCI portfolio of investigator-initiated research and remains our number one 

priority. The Human Genome Project exists at the other end of the spectrum — a large consortium of 

investigators and an initiative that produced massive amounts of uniquely valuable data, generated using 

expensive, high technology instrumentation. We now appreciate how necessary these large endeavors are, 

but the difference in scale threatens to create the scientific equivalent of the “digital divide.” The challenge is 

to balance the flow of resources to ensure that the individuals with the best ideas continue to have access 

to the resources they need. 

In recent years, NCI has expanded funding for a variety of large-scale initiatives to capitalize on the insights 

and tools derived from genetics research, proteomics, functional imaging, nanoscience, laboratory and clinical models, and targeted drug discovery and development. The success of such large-scale approaches, 

The Nation’s Investment in Cancer Research 
A Plan and Budget Proposal for Fiscal Year 2004 29

fostered by NCI’s Activities to Promote Research Collaborations Program. 

■ Expand researcher access to central resources such as databases, tissue banks, and 

animal models using funding supplements; centers, networks, and consortia; and 

cooperative resource programs. 

■ Expand researcher access to technologies that promote interdisciplinary research 

and collaborations and to the expertise needed to move discoveries to application. 

■ Develop and make available information technology tools to foster and enhance 

interdisciplinary communication and collaboration. 

■ Expand the funding for collaborative research awards such as program project grants 

and cooperative agreements for consortia that facilitate translational research. 

■ Expand the use of exploratory grants to encourage more patient- and populationbased research. 

4. Use regular and special award mechanisms to encourage investigation in priority areas identified by advisory committees, NCI staff, 

Progress Review Groups, and other groups. Leverage resources 

for these efforts through collaborative initiatives. 

■ Monitor investigator-initiated research to assess whether these projects alone are 

meeting programmatic objectives, such as those identified in specific disease areas. 

■ Set aside 10 to 15 percent of funds for Requests for Applications in specifically 

targeted areas of need. 

■ Support Program Announcements and investigator-initiated projects that target identified gaps and/or emerging opportunities (e.g., as identified by the Progress Review 

Groups and other priority setting and strategic planning activities). 

■ Enhance coordination within and among initiatives, and increase management and 

support commensurate with the growth of the portfolio. 

■ Use supplemental awards to encourage outreach to establish public-private partnerships and to leverage current NCI funded activities with new, complementary 

non-NCI sources of support. 

Management and Support $ 2.00 M 

Total $ 69.89 M 

BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

however, increasingly will require individual investigators to prosper by working in conjunction with others 

to have access to specialized facilities needed to compete. Therefore if individual grants are to continue 

to lead the way in innovation, NCI infrastructure models must have the capability of marrying individual 

expertise and imagination to state-of-the-art resources. 

To assure such balance is maintained, NCI staff work to provide broad access to NCI-funded resources, 

where possible, and to ensure that individual researchers are aware of all the resources available to 

them. But other related initiatives that provide infrastructure assets such as large-scale instrumentation 

and bioinformatics support are also integral to maintaining investigator-initiated research. Reasonable 

growth in average costs, flexible funding options, and full funding for R01s are essential to maintaining 

access to such technologies to ensure that the next generation of creative investigators working on 

cancer continues to flourish in independent settings. 
Identifying and Supporting 

High Priority Research 

NCI takes extra steps to identify and support high


priority research by:


■ Seeking out and supporting compelling research


proposals with exceptions funding, particularly 

those suggesting dramatically new or unconventional approaches to understanding cancer. 

■	 Giving special consideration to proposals responsive to high-priority research areas identified by 

NCI advisory groups, to NCI Program 

Announcements of priority research areas, and to 

recommendations from Progress Review Groups 

for research related to specific cancers. 

We are also exploring better ways to define and promote the exploration of uncharted areas and to give 

them heightened consideration when reviewing 

grant applications. 

Maximizing the Ability to Start 

New Projects and Collaborations 

NCI maximizes the pace of discovery by providing 

a broad range of flexible funding options and 

promoting collaborations and resource sharing 

wherever possible by: 

■	 Providing opportunities for collaborative study 

through awards such as program project grants 

(P01s) and cooperative agreements, in addition to 

the traditional research project grants (R01s) that 

make up the bulk of NCI’s research portfolio. 

■	 Expanding the use of award mechanisms that 

provide seed funds for promising research. 

In Fiscal Year 2001, the number of small (R03) 

and exploratory/developmental (R21, R33) 

grants awarded increased more than 15 percent 

over the previous year. 

■	 Making “administrative supplement” funds 

available to investigators to allow them to take 

advantage of unanticipated opportunities or to 

pursue interdisciplinary collaborations. For 

example, through NCI’s Activities to Promote 

Research Collaborations Program, grantees can 

apply for funding in support of collaborations to 

initiate novel research that pursues unforeseen 

opportunities and to share resources, develop 

new technologies, or organize cross-disciplinary 

meetings or workshops. 

■	 Promoting collaborative studies and sharing of 

resources through innovative networks and 

consortia. (See pages 32-35.) 

30 The Nation’s Investment in Cancer Research 

Better Understanding the Cell Microenvironment Holds Promise for More Effective Cancer 

Treatment and Prevention 

For many years, scientists have conducted studies of cells by removing them from their natural surroundings, assuming that 

the proteins, accessory cells, and blood vessels within a cell’s immediate surroundings — its microenvironment — provide 

nourishment and support with little effect on the cell’s function. But scientists now know that a cell and its microenvironment 

have a dynamic and intimate relationship. In the embryo, this relationship ensures that organs develop properly. In the adult, 

it helps to maintain the stability needed for cell functioning and influences a host of cell activities, such as proliferation and 

programmed cell death. 

The cell-microenvironment relationship also plays an important role in cancer development and progression. When 

a lone cancer cell arises from multiple changes in its own genes, it does not pose a threat to the body. But when it progresses to a tumor mass comprised of cancer cells and cells from the surrounding environment, it becomes a serious 

health concern. Researchers have observed that: 

■ The abundance of growth factors in the microenvironment provides a readily available source of growth-promoting 

signals to tumor cells. 

■ The influence between the microenvironment and cancer cells is bi-directional. Scientists must now determine whether 

neighboring cells lose their natural capacity to suppress cancer cell growth or whether they acquire an attribute that 

permits tumor growth. 

■ An enzyme induced in inflammatory cells found in the microenvironment appears to be the elusive “angiogenic switch” 

that turns on the formation of new blood vessels needed to keep cancer cells alive. 

This broadened concept of cancer has taken us from focusing exclusively on the cancer cell to exploring how the interplay 

between the cancer cell and its immediate environment supports tumor growth. Ultimately, this will enable us to explore the 

impact of tumor growth on the entire body. Rather than targeting the cancer cell alone, new prevention and treatment 

approaches will potentially target the features of the microenvironment that allow tumors to develop and progress. 

For information on NCI’s future plans for research in this area, see pages 55-59. 
Increased Investment Strengthens Research 

Training and Career Development 

Rapid developments in the frontiers of molecular biology and translational medicine have broadened the scope of disciplines needed for cancer research and have presented new challenges for 

well trained scientists prepared to tackle emerging questions in basic, clinical, behavioral, and applied 

students and scientists in pursuing careers in cancer research. This strategic plan became the foundation for the goals and objectives outlined in NCI’s Challenge Area for Research Training and Career 

Development, a component of NCI’s Plan and Budget proposal since Fiscal Year 1999. NCI is not 

requesting budget increases in this area for 2004, but we continue to use multiple strategies to 

ensure a future of talented, diverse, and innovative cancer researchers to meet the needs of the 

ever changing cancer research environment. 

Progress Report for NCI Challenge: 

Cancer Research Training and Career Development 

■ Career Awards and National Research Service 

Awards are flexibly administered to meet the 

various needs of researchers ranging from predoctoral candidates who need mentoring to 

established scientists who are leaders and 

resources in their fields. 

■ The NCI Transition Career Award provides 

“protected” time to postdoctoral trainees as 

they transition to independence and to newly 

autonomous investigators as they start to develop 

their first independent research programs. 

■ New Diversified Career Development Awards 

attract scientists in disciplines not traditionally 

associated with cancer research but clearly 

needed for the future. 

■ Supplemental funding to existing training programs through the Continuing Umbrella of 

Research Experiences Program and the 

Comprehensive Minority Biomedical Branch 

increases the pool of underrepresented minority 

candidates in the biomedical pipeline from high 

school through advanced research training. 

■ Collaborations between Minority-Serving 

Institutions and NCI-designated Cancer Centers 

support minority scientists and projects that 

focus on cancers that disproportionately affect 

minority populations. 

■ The career development program through 

Specialized Programs of Research Excellence 

supports the recruitment or reorientation of laboratory and clinical scientists to translational 

research on human cancer. 

■ Twenty Institutional Clinical Oncology Career 

Development Programs prepare clinical 

scientists to design and implement hypothesisbased clinical trials and collaborate with basic 

scientists. 

■ The Cancer Education Grant Program is aimed 

to decrease cancer incidence, morbidity, and 

mortality. 

■ 

Program encourages institutions to develop programs dedicated to training investigators at the 

predoctoral and postdoctoral level in highly 

and control; population sciences; molecular 

epidemiology, pathology, and pharmacology; 

and imaging. 

collection to provide information about students 

to quantify fulfillment of future training requirePh.D. recipients in the behavioral and biomedical 

National Research Service Awards support, to their 

colleagues without this support. Data show that in 

most respects these award recipients outperform 

their peers. 

For additional information on research 

training, career development, and educational 

opportunities available through NCI, 

go to cancertraining.nci.nih.gov. 

training future cancer researchers. In 1998, NCI launched a strategic plan for ensuring a future cadre of 

cancer research. Equally important was ensuring a future that included broader participation of minority 

at developing innovative educational approaches 

The Cancer Education and Career Development 

interdisciplinary areas such as cancer prevention 

NIH supports the development of Web-based data 

and postdoctoral trainees. This information can help 

ments. For example, a recent NCI report compares 

sciences, who have received at least nine months of 

PROGRESS REPOR T 

A Plan and Budget Proposal for Fiscal Year 2004 31
NCI Challenge: Building Our Capacity for the Future 

Expanding the Capacity of Centers, 

GOAL 

Create and sustain infrastructures that facilitate research 

collaboration, serve as 

platforms for technology 

development, and provide 

access to the full range of 

research resources. 

Networks, and Consortia 

The Challenge 

Today’s cancer researchers cannot excel in an intellectual or administrative vacuum. To maximize innovation, researchers must work effectively in an interdisciplinary environment that allows and encourages 

them to engage in newly emerging areas of research 

and technology development and to take full advantage of opportunities to move science forward to 

benefit patients and the public health. They need 

sophisticated tools, extensive — and expensive — 

information resources, and trained associates to make 

meaningful progress. And they need research infrastructures that promote collaboration in basic, clinical, and population research and among scientists in 

fields such as physics, computer science, and engineering. Investigators must have access to patients 

and at-risk populations as well as to tissue banks, 

new technologies, and state-of-the-art informatics. 

And we must establish more effective linkages 

among oncologists, researchers, the pharmaceutical 

industry, cancer advocates, and policy makers to 

ensure that the results of discovery and intervention 

development reach those people who need them. 

NCI’s challenge is to address these critical needs by 

continuing to expand the capacity of centers, networks, and consortia to most effectively: 

■ Build and sustain research infrastructures that 

encourage and reward multidisciplinary research 

and scientific collaborations. 

■ Broaden the geographic distribution and impact 

of NCI-designated Cancer Centers. 

■ Improve the access of underserved populations 

to state-of-the-art research and resources. 

■ Engage in new areas of research and technology 

development. 

■	 Make expertise, facilities, clinical practice and 

public health guidelines, and other resources 

broadly available to physicians and other caregivers, patients and families, and appropriate 

health agencies. 

Progress Toward 

Meeting the Challenge 

Building and Sustaining Infrastructures 

for Translational Research 

NCI’s overarching structure for research supports 

NCI-designated Cancer Centers, Centers of 

Research Excellence, research networks and consortia, as well as individual investigators. This framework helps create an environment conducive to 

complex scientific interactions, provides the 

resources essential for the research, and encourages 

the easy exchange of information and ideas. The 

challenge of the future will be to ensure that our 

numerous interactive linkages function at peak 

effectiveness, allowing investigators to seek answers 

to major questions more efficiently and effectively. 

Within this structure, there are several levels of 

interaction. NCI-designated Cancer Centers 

organize and integrate multidisciplinary research 

across departments and schools within a single institution or consortium of institutions. They provide 

scientists access to the most advanced technologies 

and new research opportunities. 

These Centers, in turn, have given rise to Centers 

of Research Excellence that bring together interdisciplinary and translational research teams focused 

on specific diseases, modalities, biologic processes, 

or scientific areas. They are awarded sizeable 

amounts of flexible funding to enable them to 

rapidly address emerging scientific opportunities. 

■ Specialized Programs of Research Excellence 

(SPOREs) provide platforms for interaction, 

collaboration, and intervention development for 

specific cancers. They serve as highly effective 

hubs for translational research, moving discoveries 

among laboratory, clinic, and population research 

settings. In just 10 short years this program has 

grown substantially, with 40 SPOREs conducting 

and facilitating translational research in brain, 

breast, gastrointestinal, pancreatic, genitourinary, 

32 The Nation’s Investment in Cancer Research 
head and neck, lung, lymphoma, ovarian, 

prostate, and skin cancers.1 

■	 Modeled on the SPORE blueprint, other strategic Centers of Research Excellence include 

Transdisciplinary Tobacco Use Research 

Centers, In Vivo Cellular and Molecular Imaging 

Centers, Interdisciplinary Research Teams for 

Molecular Target Assessment, and Centers of 

Excellence in Cancer Communications 

Research. The newest of these are the interdisciplinary Centers for Population Health and 

Health Disparities.2 

NCI is working to build better ways for these 

Centers of Research Excellence to share data, 

research concepts, and mechanisms for developing 

interventions. It is through these collaborative 

efforts that NCI can further leverage its resources 

and ensure the best stewardship of Federal funding. 

NCI-supported networks and consortia are also 

integrated with Cancer Centers and other programs 

in important ways. 

■	 Special Populations Networks for Cancer 

Awareness Research and Training build relationships between large research institutions and 

community based programs to find ways of 

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

■	 Through the NCI Minority Institution/Cancer 

Center Partnership program, Cancer Centers 

are developing long-term relationships with 

the Minority Serving Institutions to increase 

research, training, and outreach dedicated to 

reducing the disproportionate cancer incidence 

and mortality in minority populations. Five of 

these partnerships have been initiated to date 

and other collaborative efforts are underway 

through planning grants. 

■	 The Cancer Genetics Network is a national 

network of researchers located in NCI-designated 

Cancer Centers who specialize in the study 

of inherited predisposition to cancer. 

■	 The Mouse Models of Human Cancers 

Consortium, a valuable resource for cancer 

researchers engaged in a variety of basic, translational, clinical, and epidemiological investigations, has components in Cancer Centers. 

Consortium participants collaborate with investigators in the NCI Director’s Challenge program, 

the SPOREs, and the Early Detection Research 

Network (EDRN)3 to evaluate various highthroughput technologies to ensure that compatible technologies are developed for mouse 

research. 

■ Further interactions are ongoing among EDRN 

investigators, SPORE investigators, and other 

interdisciplinary groups to facilitate the discovery, development, and initial steps in clinical 

validation of molecular markers and assays that 

detect early signs of cancer. 

Bringing State-of-the-Art Research 

Results to Cancer Patients 

NCI-supported Cancer Centers, networks, and 

consortia can serve as natural hubs for national 

leadership in the war against cancer and provide a 

means for fostering coalitions and partnerships with 

other cancer funding organizations, professional 

societies, businesses, industry, communities, and 

local and state governments. 

In the last five years, more than 40 of the 60 Cancer 

Centers have received the “comprehensive” designation. This includes most medical institutions in 

the United States with major biomedical research 

programs. Directors and investigators at these 

Comprehensive Cancer Centers participate proactively with NCI in outreach activities to more rapidly bring the benefits of research to patients, 

physicians and other caregivers, and communities, 

especially to those in under-represented geographic 

regions of the Nation. NCI is working to facilitate 

the establishment of regional cancer centers — 

partnerships between smaller institutions and the 

large, existing NCI-designated Comprehensive 

Cancer Centers — to provide patients and populations with much improved access to the newest 

trials in early detection, prevention, and therapeutic 

research. 

In the summer of 2002, The National Cancer 

Advisory Board assembled an Ad Hoc working 

group to establish a blueprint for NCI-designated 

Cancer Centers and SPOREs. The Ad Hoc group 

was charged with considering strategies for balancing the breadth and depth of the centers program, 

maximizing translation of research discoveries, 

developing objectives of a national cancer agenda 

focused on reducing the cancer burden, and facilitating partnerships with other governmental, private, philanthropic, and industrial entities. 

Recommendations from the working group are 

expected in early 2003. 

BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

33 

1 spores.nci.nih.gov


2 See page 84 for more information.


3 cancer.gov/prevention/cbrg/edrn


A Plan and Budget Proposal for Fiscal Year 2004 
The Plan 

Expanding the Capacity of Centers, Networks, and Consortia 

GOAL 

Create and sustain research infrastructures and collaborations that enable multiple scientific 

disciplines to address large problems in human cancer that cannot be solved by individual 

investigators. Promote networks, partnerships, and coalitions that increase the pace of 

translational research and the rate at which the results of research are translated into 

clinical practice and public health benefit. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Increase the number and geographic distribution of $ 6.25 M 

NCI-designated Cancer Centers. 

■ Designate one new Cancer Center. 

■ Bring Cancer Center resources and expertise to two regions of the country with 

large underserved populations by designating two specialized Centers or by direct 

partnerships between regional institutions and existing Comprehensive 

Cancer Centers. 

■ Award two new Cancer Center Planning Grants to institutions in areas of the 

country not currently served by Cancer Centers. 

■ Plan a new Cancer Center consortium mechanism in regions of the country in 

which no single institution has the research strength to become a traditional 

NCI-designated Cancer Center. 

2. Encourage collaborations and partnerships to improve access of $ 6.00 M 

minority populations to state-of-the-art clinical and population 

studies, cancer treatments, technologies, and care. 

■ Continue to support formal partnerships between Cancer Centers and Minority 

Serving Institutions in the form of two comprehensive partnerships and one 

planning grant to enhance the research capabilities of the institutions and 

improve the effectiveness of Cancer Centers in serving minority communities. 

$5.50 M 

■ Integrate NCI-designated Cancer Centers and Minority Institution/Cancer Center 

Partnerships with the NCI Special Populations Networks for Cancer Awareness 

Research and Training. $0.50 M 

3. Expand the capacity of NCI centers, networks, and consortia to $51.08 M 

engage in newly developing areas of research and technology and 

to act as platforms for translating discoveries into interventions. 

■ Provide additional funding to build the clinical research and population research 

infrastructure of NCI-designated Cancer Centers. Fund databases that conform 

to NCI’s clinical informatics infrastructure; support the development and expansion 

of population databases and other resources; provide more core staff to conduct 

innovative translational therapeutic and prevention trials; and strengthen the 

auditing and data safety and monitoring of human subjects research to conform to 

Federal regulations. 

34 The Nation’s Investment in Cancer Research 

$1.50 M 

$2.50 M 

$0.75 M 

$1.50 M 

$15.00 M 
■ Promote and develop matching fund and co-funding partnerships of NCIdesignated Cancer Centers with industry and national, private, state, and 

community organizations, as well as with other cancer funding organizations, 

to expand the conduct and impact of translational research. 

■ Encourage NCI-designated Cancer Centers, networks, and consortia to network 

with each other to integrate best practices, share protocols, and maximize 

collaborative research opportunities and avoid duplication of resources. 

■ Build on NCI’s Prostate, Lung, Colorectal, and Ovarian Screening Trial to 

develop an Early Detection Cancer Screening Trials Network to expand and 

accelerate laboratory and clinical research and the application of early detection 

technologies. $0.08 M 

■ Encourage collaborations among NCI-supported research centers, networks 

and consortia involved in translational research, including Cancer Centers, 

Specialized Programs of Research Excellence (SPOREs), Transdisciplinary 

Tobacco Research Centers, the Cancer Genetics Network, Clinical 

Cooperative Groups, Special Population Networks, the Early Detection 

Research Network, and the Mouse Models of Human Cancers Consortium. 

$0.50 M 

■ Expand the SPORE program by adding one SPORE each for gastrointestinal, 

brain, head and neck, and leukemia and lymphoma cancers; and two 

SPOREs each for ovarian and skin cancer. 

■ Establish a protected Web-based system for SPOREs, to exchange work in 

progress and research results to enhance inter-SPORE research. 

■ Expand the supplement programs for SPOREs, to stimulate inter-SPORE 

research projects and to conduct early clinical trials. 

■ Support expansion of infrastructure and methods for evaluating large 

scientific initiatives for translational research. 

4. Expand the capacity of NCI Cancer Centers, networks, and $ 15.00 M 

consortia to disseminate proven interventions into communities 

and populations. 

■ Provide additional funding and seek funded partnerships with government 

and non-government organizations to perform research into cost-effective and 

efficacious dissemination of validated interventions for prevention, early 

detection, and treatment to practitioners, communities, and populations. 

$7.00 M 

■ Design ongoing Cancer Center infrastructure and mechanisms for practitioner, 

community, and population outreach to enhance the Cancer Centers’ 

leadership role in disseminating proven interventions for cancer prevention 

and care for all. 

Management and Support $ 1.20 M 

Total $ 79.53 M 

BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

A Plan and Budget Proposal for Fiscal Year 2004 35

$5.00 M 

$0.50 M 

$24.00 M 

$0.50 M 

$5.00 M 

$0.50 M 

$8.00 M 
NCI Challenge: Building Our Capacity for the Future 

National Clinical Trials Program in 

GOAL 

Ensure that clinical trials 

address the most important 

questions in treatment and 

prevention, are broadly accessible, and enable strong translational research. 

Create flexible mechanisms that allow for easy


cooperation among basic scientists, clinicians,


industry, academia, and NCI.


Explore how molecular targeted therapies can be


used in combination with conventional treat­


ments or other molecular targeted agents.


Develop surrogate endpoints3 to improve the


efficiency of small translational trials.


Identify the most promising treatment or pre­


vention agents for movement into large, easily


accessible trials.


Improve support to physician researchers.


Improve access to clinical trials by physicians


and their patients.


Help ensure that treatments are made available


to all patients who need them.


Treatment and Prevention 

The Challenge 

As we decipher the molecular changes that cause a


cell to become cancerous, a new paradigm in cancer


treatment and prevention is emerging. Increasingly,


new anti-cancer agents are directed at distinct


molecular targets present within cancer cells, leav­


ing healthy cells unharmed.1 In light of the unique


challenges arising from this paradigm shift, NCI


must provide a versatile clinical trials system that


will quickly and safely move proven anti-cancer


interventions into healthcare settings where


patients will benefit. 


NCI provides leadership, resources, and expertise 


at all stages of clinical development for molecularly


targeted agents. In the early stages of research,


when candidate drugs are identified and shown to


have promising potential, NCI forms collaborations


and partnerships that help researchers from public,


industrial, and academic settings to develop cancer


fighting agents for a broader array of tumor types


and at a faster pace than would otherwise be possi­


ble. After establishing proof-of-principle2 in early


clinical trials, researchers move on to verify the


presence of relevant molecular targets in popula­


tions of patients and test for improvements in 


outcomes, such as tumor response, time to tumor


progression, and improved survival. During this


stage, NCI provides resources to test promising


leads in large numbers of patients. 


NCI has made substantial progress in building a


clinical trials system that meets these requirements.


However, a number of critical issues remain to be


addressed. We must:


■ Identify the most important questions in preven­


tion and treatment that can be addressed 

through clinical trials. 

■ 

■ 

■ 

■ 

■ 

■ 

■ 

Progress Toward 

Meeting the Challenge 

Building the Capacity for Successful 

Clinical Trials Research 

As more private sector companies are beginning to 

develop anti-cancer drugs, NCI is expanding its role in 

public-private partnerships. Because pharmaceutical 

companies tend to seek FDA approval or licensing of 

a new agent for a single or few tumor types, NCI can 

help ensure that new agents are evaluated against a 

fuller range of cancers (or pre-cancers) and in combination with treatments such as surgery, radiation therapy, 

or other drugs. In one recent success, the collaboration between Novartis Pharmaceuticals and 

NCI-supported researchers led to the development of imatinib (previously called GleevecTM) to treat 

chronic myelogenous leukemia and now gastrointestinal stromal tumors.4 In another public-private 

partnership, the arthritis drug celecoxib is being 

tested as a targeted drug for colorectal cancer 

prevention and treatment. 

1 See Molecular Targets of Prevention and Treatment, pages 60-64.
 2 In proof-of-principle studies investigators demonstrate that an agent has the desired biological effect on its target.
 3 Surrogate endpoints are based on laboratory measurement of some biological indicator of a drug’s effectiveness rather than on longer-term outcome measures.
 4 See sidebar, this chapter.


36 The Nation’s Investment in Cancer Research
NCI also recognizes the increasing need for collaboration with laboratory scientists in conducting 

clinical trials for molecular targeted agents. 

The cellular pathways and interactions involved in 

these molecular targets are extraordinarily complex 

and inter-related, and they require scientists to 

develop new techniques and tests to identify 

patients whose tumors contain the relevant targets 

and to monitor drug effects during treatment. More 

than half of NCI-sponsored cancer treatment trials 

initiated over the last two years have included correlative studies with laboratory scientists and this 

trend is increasingly seen in cancer prevention trials. 

NCI continues to simplify the administration of 

clinical trials to make it easier for physicians and 

their patients to participate in NCI-supported trials. 

In 2000, we launched the online Cancer Trials 

Support Unit (CTSU) site to centralize the common administrative, financial, and data collection 

activities of its clinical trials cooperative groups. 

Since May 2002, CTSU physicians outside NCI 

cooperative groups have also been able to enroll 

patients into these NCI-sponsored clinical trials. 

NCI’s efforts are having a noticeable effect, with 

accrual to NCI-sponsored cancer treatment trials 

increased by an unprecedented 18 percent in 2001. 

Making Strides in Cancer Treatment 

through Clinical Trials 

NCI’s focused investment in clinical trials is paying 

off with increased survival and better quality of life 

for patients with a variety of cancers. Just a few of 

the advances emerging from recent clinical trials 

are listed here: 

■ Adjuvant therapy with oxaliplatin provides a 

modest survival advantage to some colorectal 

cancer patients who undergo conventional 

chemotherapy.

6 

■ Tamoxifen, a targeted agent that has been 

shown to improve survival in some women with 

breast cancer when given together with 

chemotherapy, improves disease-free survival 

even better if given when chemotherapy has 

been completed. 

■ Treatment with high doses of the drug methotrexate improves the event-free survival of children 

with T-cell acute lymphoblastic leukemia (ALL) 

as well as or better than any other drug reported in 

the medical literature. 

the type of research that has led to a 75 percent 

decline in mortality rate for children with ALL 

over the last 27 years, through improvement of 

conventional cancer therapies. 

Making Strides in Cancer 

Prevention through Clinical Trials 

From years of scientific research, we know that 

cancers are not caused by a single, catastrophic 

event, but result from a complex and long-evolving 

process. Since many cancers take decades to 

develop, we have the time and opportunity to 

intervene to stop or reverse its progress before 

patients become sick. NCI’s clinical trials for cancer 

Treatment with Imatinib Builds on Early Success 

In May 2001, the U.S. Food and Drug Administration (FDA) gave fast track approval to the molecularly targeted drug imatinib (then called GleevecTM or STI571) for the treatment of chronic myelogenous leukemia. 

Imatinib blocks the cancer causing effects of a genetically altered protein commonly found in this disease.5 

More recently, the FDA approved imatinib for treatment of gastrointestinal stromal tumors (GIST), a cancer 

caused by genetic modification of another imatinib-sensitive protein. GIST is a relatively uncommon but 

high-mortality cancer, notoriously resistant to any kind of chemo- or radiation therapy. When given to GIST 

patients in clinical trials, imatinib either dramatically reduced tumor size or arrested tumor growth. Clinical 

trials are underway to test the use of imatinib in treating over 15 other cancers. Some patients have already 

responded remarkably, including a chronic myelomonocytic leukemia patient whose blood was completely 

cleared of cancer in only one month. 

Despite these unprecedented successes, researchers are finding that, for a number of reasons, many 

patients with advanced stage disease eventually stop responding to imatinib therapy. Based on intensive 

research, investigators are identifying strategies to overcome imatinib resistance, including treating patients 

with a combination of molecular targeted drugs early in the course of their illness. 

5 For more detail on this Story of Discovery, go to plan2003.cancer.gov. 

The trial is an example of 

37 BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

6 See page 11 for more information. 

A Plan and Budget Proposal for Fiscal Year 2004 
The Plan 

National Clinical Trials Program in Treatment and Prevention 

GOAL 

Ensure that NCI’s clinical trials program is poised to address the most important medical and 

scientific questions in cancer prevention and treatment quickly and effectively through state-ofthe-art clinical trials. Ensure that the trials are broadly accessible to cancer patients, populations 

at risk for cancer, and the physicians who care for them. Incorporate relevant correlative 

laboratory studies into clinical trials to enable strong translational research. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Identify and develop the most promising new agents for cancer treatment $84.50 M 

and prevention. 

■ Expand partnerships and create flexible collaborations with industry, the FDA, and other 

public, private, and academic organizations to speed development of promising agents 

and to bring together the best laboratories, institutions, and investigators (including 

surgeons, pathologists, and radiologists, in addition to traditional participants) for early 

translational research. 

■ Expand resources for the Rapid Access to Intervention Development and Rapid 

Access to Prevention Intervention Development programs. (See page 62, Objective 4.) 

■ Expand capacity to file Investigational New Drug Applications and New Investigational 

Technology Applications to facilitate early proof-of-principle clinical trials. 

■ Create broadly based working groups to identify clinically relevant surrogate endpoints. 

Develop resources and standardize assays, approaches, and clinical trial designs to validate 

these endpoints. 

■ Build translational research capacity to use correlative studies more extensively. 

■ Increase funding for Interdisciplinary Research Teams for Molecular Target Assessment 

to develop resources to assess the effects of promising agents on their molecular targets. 

$20.00 M 

■ Develop molecular assays required to characterize/classify tumors, and make them widely 

available. (See page 62, Objective 2.) 

facilitate rapid evaluation of new assays and relevant clinical correlations as new targets 

are identified. 

■ Increase the pace of development and clinical testing of promising new therapeutic and 

preventive agents by (1) substantially increasing the number of promising agents entering 

NCI-sponsored clinical trials over the next two to three years as well as the number of 

pivotal early clinical trials, (2) tripling annual patient accrual to early clinical trials of 

promising agents, (3) providing financial incentives for timely initiation of clinical trials 

and adherence to developmental milestones, and (4) expanding the rapid grant review 

process, Quick Trials, for mechanism-based clinical trials. 

■ Support the NCI intramural clinical trials program by increasing the number of data 

managers, research nurses, biostatisticians, and clinicians available to support a critical 

mass of clinical investigators, and continuing the Tissue Array Research Program to 

identify key molecular alterations in cancers. 

2. Strengthen scientific planning and leadership for the large, definitive $26.00 M 

clinical trials that evaluate and define the efficacy and clinical benefit of 

new treatments and prevention strategies. 

■ Identify and address compelling clinical questions confronting physicians and their 

patients under treatment for cancer or at high-risk of cancer. 

38 The Nation’s Investment in Cancer Research 

$4.00 M 

$0.50 M 

$2.00 M 

$8.00 M 

Support a national tissue resource system to 

$35.00 M 

$15.00 M 

$17.00 M 
A Plan and Budget Proposal for Fiscal Year 2004 39

■ Expand State-of-the-Science meetings to identify important research questions and 

define a scientific research agenda to address them. 

■ Expand clinical trials planning to address critical questions across the major types 

of conditions experienced by patients by (1) integrating cross-disciplinary input 

(e.g., oncology and diagnostic imaging) and project teams into scientific strategic 

planning and (2) incorporating evaluation of relevant biomarkers as well as behavioral, 

epidemiologic, outcomes, and other research into existing treatment and prevention 

trials to address questions in specific tumor types and patient populations. 

■ Provide additional research funds for leadership support of scientists who are 

responsible for writing, monitoring, and analyzing NCI-sponsored, high-priority 

Phase III trials: researchers who chair studies in addition to caring for patients, 

and study statisticians. 

■ Increase funding for tissue banks (collection and storage of patient tissues from large 

clinical trials with accompanying patient data). This will enable correlative studies and 

long-term follow-up for future evaluation of new assays and markers. 

3. Double the rate at which Phase III trials are completed. $223.50 M 

■ Increase the number of patients accrued to national trials, and shorten the duration 

of accrual, to substantially increase the number of new treatments or interventions 

that can be evaluated. Increase funding for nursing, data management, and other 

infrastructure costs at local clinical trial sites, and for operations, data management, 

and statistical offices. Increase the number of (and the capacity of existing) 

Community Clinical Oncology Programs. 

■ Facilitate participation of new clinical trials investigators through a “start-up” loan 

program (repayable by reduced future reimbursements) for training, research nurse 

support, and data management. 

■ Provide extensive information about treatment and prevention clinical trials to enable 

patients and physicians to make informed choices. With the NCI Office of 

Communications, patient advocacy groups, and others, create educational, marketing, 

and communications strategies to inform patients and physicians about clinical trials. 

Develop novel strategies, including the use of alternative media, for working with 

minority and under-represented patient populations and their primary care physicians. 

■ Expand the Cancer Trials Support Unit to consolidate administrative tasks and to 

provide a single interface for investigators to enroll patients. Develop uniform electronic case report forms and data reporting systems. Expand NCI’s audit program to 

ensure continued high quality accurate data from new sites and increased accrual to 

clinical trials. 

■ Provide funding directly to participating patients with special needs to cover costs 

associated with travel, childcare, and other relevant limiting expenses. Work with state 

and local government agencies to address barriers to access for patients dependent on 

state health agencies for healthcare coverage. 

4. Reduce outcome disparities caused by lack of access to trials or 

follow-up care. 

■ Increase access of underserved populations to state-of-the-art clinical trials. 

(See page 87, Objective 4). 

■ Encourage local sites to identify existing resources for helping underserved patients 

receive appropriate follow-up care and ensure that follow-up care is offered. 

Management and Support $ 6.10 M 

Total 340.10 M 

BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

$1.00 M 

$1.00 M 

$3.00 M 

$4.00 M 

$ 
The Next Step in Targeted Therapy — Hitting Multiple Targets 

Scientists know that cancer develops as a result of mutations in genes that in turn alter the normal structure of certain proteins (those that regulate cell growth and other critical functions). These genetically 

altered proteins disrupt “cellular pathways,” or the ordered interactions among the diverse molecules in 

the cell, resulting in uncontrolled cell growth and cancer. As scientists gain a better understanding of these 

molecular changes, they are able to develop drugs designed to stop cancer development in its tracks by 

targeting the faulty proteins that wreck havoc on normal cellular pathways. 

Increasingly, however, investigators are learning that targeting one protein or one pathway is not always 

enough. Cellular pathways are tremendously complex, involving intricate and ordered contact among thousands of molecules. As one targeted pathway is shut down within its cells, the tumor may begin to die, 

but then start growing again. It may be that an alternate pathway, one not affected by the drug, is able 

to perform the same function as, and thus compensates for, the targeted pathway. This type of “cellular 

redundancy” occurs naturally and, although it is healthy and beneficial in normal cells, it makes cancer 

cells harder to kill. To contend with this reality, researchers have begun developing drug treatments that 

use combinations of targeted drugs to simultaneously shut down alternate pathways so that the cell 

cannot escape the effects of treatment. Furthermore, since some patients are resistant to one type of 

drug but not another, using combinations of drugs targeting critical junctures of multiple pathways should 

increase the patient’s chances for successful treatment. 

prevention seek to determine which person is at 

risk for cancer; define ways to prevent or reduce 

that risk; detect cancer at its earliest stages; and 

actively intervene to prevent invasive cancer. The 

following represent a small sampling of the progress 

in these areas: 

■	 Because some women suffer serious side effects 

from tamoxifen, NCI is sponsoring clinical trials 

for other preventive agents, such as raloxifene, 

an osteoporosis prevention drug. NCI-supported 

researchers are also developing risk assessment 

tools to determine which patients are most likely 

to benefit from various prevention strategies 

with the fewest side effects. 

■	 The newest prostate cancer prevention trial, the 

Selenium and Vitamin E Cancer Prevention 

Trial, was launched in July 2001. The 12-year 

study will answer whether or not seven or more 

years of daily dietary supplementation with selenium and/or vitamin E will reduce the incidence 

of prostate cancer. Of note, one third of the 

32,400 men needed were accrued within the first 

eight months of the trial. Serum and white blood 

cells are being collected for correlative laboratory 

research and preliminary results from early studies are encouraging. Studies examining cells 

grown in the laboratory have suggested that 

selenium might slow the growth of prostate 

cancer and kill the cancerous cells by apoptosis 

— a cell suicide mechanism. 

■	 Investigators recently discovered that patients 

with a history of colon polyps might reduce their 

risk of developing colon cancer by taking low 

doses of aspirin in addition to having their 

regular colorectal cancer screenings. 

40 The Nation’s Investment in Cancer Research 
A Plan and Budget Proposal for Fiscal Year 2004 

Drug Discovery and Development — A Life Saving Investment 

Spotlight on Research 

Discovering and developing new treatments for cancer is a lengthy and expensive process. But 

therapeutics that use the latest knowledge and the best technology are absolutely essential for us to 

move forward in our fight against cancer. The process begins in laboratories at university, research 

institute, government, or industrial facilities where individual or groups of scientists identify possible 

drug agents to target cancer. Once identified as potential agents, compounds must be screened, 

tested, and used successfully without serious adverse effects in clinical trials. 

Preclinical testing validates the 

safety and biological activity of a 

compound in the laboratory and 

in animal models. Clinical trials 

determine safe and most effective dosages, how a treatment 

should be administered, its efficacy, and patient outcomes. 

At any point in this drug development process, researchers 

may discover that the compound does not work in quite 

the way they were hoping. 

Animals have such intricate 

molecular biology that a drug 

that effectively disrupts cancer 

development in isolated cells 

may behave differently in a 

mouse, and differently still in a 

human. When a drug does not 

work, researchers must decide 

whether to abandon that compound or take it back to the laboratory and try to modify it. 

Once these steps are completed, new drugs must then be 

approved by the Food and Drug 

Administration through a rigorous process before they can be 

used to treat cancer. 

Only one in 5,000 compounds 

or fewer make it to FDA 

approval. The total length of 

time from initial discovery to 

FDA approval averages around 

15 years and the total cost can 

be as high as $500 million to 

develop a single new drug. 

As we attempt to design or 

discover more targeted therapeutics, the costs may be even 

higher. However, only through 

this painstakingly thorough 

process of drug discovery and 

development do the many 

lifesaving cancer drugs coming 

out every year reach the 

patients whose lives are 

touched by them. 

0 4 6 8 1 0 1 2 1 4 

years 

Identification and Preclinical Testing 

Clinical Trials 

Post-Clinical Trials 

5,000 compounds screened to identify 250 for preclinical testing 

5 of the 250 compounds advance to clinical testing 

New Drug Application or Biologics 

License Application filed with FDA 

FDA Approval for one new drug 

Laboratory/preclinical testing conducted to assess safety and biological 

activity in the laboratory and in animal models 

Phase I – 

Determines safe dosage and how treatment should be given 

Phase II – 

Evaluates effectiveness and looks for side effects 

Phase III – 

Determines whether the new treatment or new use of a 

treatment is a better alternative to the current standard 

Investigational New Drug (IND) application filed with 

the Food & Drug Administration (FDA) 

Averages 4.4 years 

Averages 1.4 years 

Averages 8.6 years 

SPOTLIGHT ON RESEARCH 

41 

2 
NCI Challenge: Building Our Capacity for the Future GOAL 

Create a cancer informatics infrastructure to 

support and integrate 

the full spectrum of 

cancer investigations. 

Developing Bioinformatics for Cancer Research 

The Challenge 

Bioinformatics is the art and science of electronically 

representing and integrating biomedical information 

in a way that makes it accessible and usable. Each 

discipline involved in the immense complex of cancer research generates volumes of data and research 

findings, all contributing vital threads of insight that 

bioinformatics specialists must weave together into 

a tapestry of knowledge. The challenge is to use 

electronic standards to devise systems that allow 

different sets of data to “talk” to one another. Such 

systems make it possible for scientists to use this 

new “in-silico” biology to generate hypotheses; conduct virtual experiments using large collections of 

data from multiple sources; and create, manage, and 

communicate massive amounts of new knowledge 

in practical timeframes. 

The challenge of integrating separate scientific 

vocabularies and insight is daunting because of the 

vastness and rapid evolution of the data. New models 

and tools are needed to allow scientists to bridge 

language, integrate concepts and information, and 

enable complex analysis. In this way, information 

systems will be a vital, dynamic tool in the hands of 

cancer researchers. To address these challenges, 

NCI is pioneering a versatile informatics infrastructure, requiring us to: 

■ Help incubate the next generation of bioinformatics applications and insights to support 

cancer research. 

■	 Establish partnerships with commercial, academic, 

and other governmental groups engaged in 

bioinformatics research and development, thus 

broadening our base of components, compatible 

tools, and data. 

■	 Expand training and support for scientists 

pioneering the application of bioinformatics in 

cancer research. 

Progress Toward 

Meeting the Challenge 

Constructing a Cancer Knowledge 

Resource 

One of our key tasks has been to develop the ability 

to classify, locate, and distribute units of cancerrelated information, such as the description of a 

gene or a process, the email address of a principal 

investigator, or a reference to a published paper. 

Data are transformed into information components, 

which can then be combined to generate knowledge. Our system is called the cancer Common 

Ontologic Reference Environment (caCORE). 

The caCORE is composed of three interacting 

layers. At its foundation is NCI’s Enterprise 

Vocabulary Services, which organize and translate 

the distinct but overlapping vocabularies of disparate scientific projects via a common vocabulary. 

The middle tier of caCORE contains ways of collecting scientific data or Common Data Elements 

that conform to the international standards used by 

other Federal organizations. This keystone effort 

will ensure that all data from NCI-supported programs, whether from clinical trials, animal model 

programs, basic research, or other disciplines can be 

easily shared. 

The top layer of caCORE is composed of models 

of information — the cancer Bioinformatics 

Infrastructure Objects (caBIO). The objects capture the expertise within the disciplines that constitute cancer research, allowing the knowledge to be 

shared through computer tools. The current collection of objects captures knowledge in the areas of 

genomics, genetics, animal models, and clinical 

trials. caBIO is built with open source software, 

making it available to scientists without restriction. 

42 The Nation’s Investment in Cancer Research 
Collecting and Sharing Cancer 

Research Data 

The data and findings produced through NCI 

initiatives are valuable not only to the investigators 

who generate them but also to other cancer 

researchers. They form a foundation on which to 

build future studies and a resource for “in silico” 

biomedical experiments. Some examples follow. 

■	 We have constructed a repository for the mouse 

models developed by the cancer research community through the Mouse Models of Human 

Cancers Consortium. The repository is called 

the Cancer Models Database.

1 It contains 

models that can be used to further explore cancer’s origins and to test new therapies. The database allows researchers to share the insights they 

have gained in their investigations. It also permits additional investigators to extend the work 

of the model generators, building directly on the 

base they have constructed and accelerating the 

rate of discovery. 

■	 We have created a repository called the Gene 

Expression Database Portal2 to provide an 

integrated system for researcher access to tumor 

genetic and molecular taxonomy data enabled 

by initiatives such as the NCI’s Directors 

Challenge: Toward a Molecular Classification 

of Cancer and the Mouse Models of Human 

Cancers Consortium. 

■	 We continue to expand the collection of publicly 

accessible genomic data generated by the 

Cancer Genome Anatomy Project and to expand 

1 cancermodels.nci.nih.gov/mmhcc 

2 gedp.nci.nih.gov 

the use of state-of-the-art informatics tools 

through collaboration with the Cancer Therapy 

Evaluation Program. 

Building a Network of Interoperable 

Analytic Tools and Data Sources 

NCI has begun the process of establishing a network of bioinformatics tools and data that interact 

to capture the innovation of the cancer research 

community and facilitate the use and re-use of its 

valuable resources, such as tissue repositories. 

■ A first step in building the network has been the 

construction of Internet portals through 

which various network and consortia communities can share their tools and data. 

■	 NCI is working with the American Association 

of Cancer Institutes to build a clinical trials 

network that distributes information, available 

to all, on those trials that are conducted at 

participating Cancer Centers. 

■	 NCI is leading a consortium of industry, academia, and government agencies to develop an 

interoperable infrastructure for biomedicine, the 

Interoperable Informatics Infrastructure 

Consortium. 

Fostering Application of In Silico 

Biomedicine in Cancer Research 

and Care 

Early applications of in silico biomedicine in cancer 

research supported by NCI confirm the promise of 

this exciting new scientific approach. These efforts 

Bioinformatics: Linchpin of Translational Science 

Translating results from the laboratory bench to bedside delivery of patient care and communicating the 

lessons learned back to the bench, goes far beyond the high-speed calculation, the once-unimaginably 

complex modeling, and the massive storage and retrieval used for individual studies in individual institutions. 

It demands a whole system of linkages across laboratories, clinics, disciplines, and organizations, from 

purely research to regulatory, to journalistic, to advocacy, and beyond. At the National Cancer Institute, we 

recognize that bench-to-bedside translation is conceptually inseparable from informatics. Our success with 

one will continue to reciprocally drive our success with the other. 

Developing the bioinformatics infrastructure requires that we build greater power and compatibility at several 

levels of focus, and at several points in the process, building pioneering systems that, in working together, 

make it easier for the scientists who use them to work together as well. The codes and logic that form the 

language for integrating these systems can then be standardized. In many cases, the standards themselves 

must be created, tested, and agreed upon. 

Research highlights in this section illustrate application of these prototype informatics systems, ranging from 

the micro level for discovering meaningful patterns in bits of genetic material to the macro for monitoring 

clinical trial activity, to the most broadly focused for tracking and comparing activity, so that we can know 

how well our funding is meeting the full range of research requirements. 

BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

A Plan and Budget Proposal for Fiscal Year 2004 43
The Plan 

Developing Bioinformatics for Cancer Research 

GOAL 

Create a cancer informatics infrastructure that enhances information and resource 

exchange and integration among researchers and clinicians working in diverse 

disciplines, to facilitate the full spectrum of cancer investigations. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Expand NCI’s core informatics infrastructure to support and integrate $ 49.00 M 

NCI-supported basic, clinical, translational, and population 

research initiatives. 

■ Provide additional support and enhance integration of data and development of tools 

emanating from NCI’s Extraordinary Opportunities. Facilitate information exchange 

within NCI-supported research initiatives. Support Specialized Programs of Research 

Excellence and Cancer Center efforts. 

■ Establish a toolbox of open-source informatics applications and services based on a 

common set of operating principles that support NCI’s diverse cancer research 

activities. 

■ Expand the research infrastructure that uses the NCI “knowledge stack,” assembling 

common vocabulary, standard data elements, and information models to further the 

exchange of all types of cancer information and data among the cancer community. 

$5.00 M 

■ Expand information technology-based support services to enhance planning, execution, and communication of the wide-ranging research portfolio supported by NCI. 

$10.00 M 

44 The Nation’s Investment in Cancer Research 

demonstrate that bioinformatics can be used to 

refine diagnosis and improve screening. 

Facilitating Discovery through Integration Tools. NCI 

has undertaken the Cancer Molecular Analysis 

Project to facilitate the identification and evaluation of molecular targets in cancer by integrating 

comprehensive molecular characterizations of cancer. Both the data and infrastructure are publicly 

accessible.3 

Improving Cancer Diagnosis and Screening through 

Bioinformatics. Recent successes demonstrate the 

immense potential for the use of bioinformatics 

tools, specifically artificial intelligence, to improve 

cancer diagnosis and screening. 

■ Effectively and safely treating pediatric acute 

lymphoblastic leukemia (ALL) requires detection of subtle distinctions among several subtypes. Pinpointing the subtype usually requires 

the combined efforts of a hematologist/oncologist, a pathologist, and a cytogeneticist. NCIsupported researchers have used artificial intelligence to analyze samples from patients whose 

diagnoses had already been determined. Their 

new test is 95 percent accurate. Moreover, they 

identified a new subtype of ALL. 

3 cmap.nci.nih.gov. The Cancer Molecular Analysis Project application permits investigators to discover molecular targets, assess their validity and interaction 

with other targets, determine if there are therapeutic agents that can act on this target, screen for possible toxicity, and determine whether there are clinical trials 

evaluating these agents. 

$29.00 M 

$5.00 M 
BUILDING THE NA TION’S CANCER RESEARCH CAP ACITY 

2. Create a community matrix of interoperable data sources, analytic $21.50 M 

tools, and computational resources that provide informatics 

capability for the cancer research community. 

■ Enable other organizations’ information systems to work seamlessly with ours. 

academic, government, and commercial strategic 

partnerships in a research park setting where all partners can work together to address bioinformatics 

questions. 

■ Use a minimum of 20 investigator-based awards that build on the NCI informatics 

core to (1) deploy resources to the cancer research community to serve as the foundation for additional infrastructure and (2) facilitate rapid deployment of related new 

research initiatives. 

3. Expand the capacity of cancer research institutions to $ 11.50 M 

perform interdisciplinary informatics research. 

■ Establish a network of bioinformatics research centers to work with and through the 

NIH Biomedical Informatics Science and Technology Initiative. 

■ Supplement funding to NCI-supported research organizations to support 

investigator-initiated research to access state-of-the-art biocomputing tools and 

data. 

4. Support bioinformatics training for both experienced and new scientists. $ 

■ Recruit new scientists through 20 development awards. 

■ Cross train experienced scientists through transition awards. 

Management and Support $ 

Total $88.00 M 

A Plan and Budget Proposal for Fiscal Year 2004 45

■ NCI scientists have analyzed microarrays using 

an artificial intelligence technology called neural 

networks to distinguish among members of a 

family of childhood tumors that include neuroblastoma, rhabdomyosarcoma, non-Hodgkin 

lymphoma, and Ewing tumors. The results of 

this kind of analysis hold promise for enabling 

healthcare providers to select appropriate treatment options and determine possible outcomes 

for patients. 

■ NCI scientists have found that patterns of 

proteins in patients’ blood serum may reflect 

the presence of disease and have used serum 

proteins to detect ovarian cancer, even at early 

stages. The research, a collaboration of the 

Food and Drug Administration, the NCI, and a 

private company, unites two exciting disciplines: 

proteomics, the study of the proteins inside 

cells, and artificial intelligence computer programs. Scientists were able to “train” the computer to distinguish between patterns of small 

proteins found in the blood of cancer patients 

and those of people not known to have the 

cancer. The artificial intelligence program 

identified exquisitely subtle differences in the 

patterns that may distinguish between women 

with ovarian cancer and women with noncancerous conditions. 

Establish a minimum of 5 

$15.00 M 

$6.50 M 

$5.00 M 

$6.50 M 

3.00 M 

$1.50 M 

$1.50 M 

3.00 M 
The Interface of Aging and Cancer 

The risk of developing cancer increases with age. Because of this vulnerability for our Nation’s aging 

population, NCI is conducting innovative research to better understand the relationships between aging 

and the development and progression of cancer. Further work is needed to fully address the interface 

of aging processes with cancer detection, diagnosis, and pre-treatment evaluation as well as the 

efficacy and tolerance of anti-cancer drugs in older patients. 

By 2030, 20 percent of the U. S. population will be 

over 65 and the number age 85 years and older will 

have more than doubled in size from 4 million to 

approximately 8.5 million. Close to 58 percent of 

all newly diagnosed malignancies and 71 percent 

of all cancer deaths are in persons 65 and older 

according to the NCI Surveillance, Epidemiology, 

and End Results (SEER) program data for 1995-

1999. As people live longer, more will experience 

cancer. As a result, there will be more cancer 

survivors, many of whom will experience residual 

problems that impact their quality of life. 

Growing older as a cancer survivor also increases 

one’s chances of developing other health problems, disabling conditions, and the recurrence 

of cancer. 

Cancer statistics, demographic projections, and epidemiologic perspectives combine to illustrate the 

need to develop cancer control and cancer research 

strategies that address the magnitude of the cancer 

problem for current and future older Americans. 

NCI and the National Institute on Aging (NIA) 

have partnered to integrate crosscutting aging and 

cancer research and focus funding within existing 

research priorities. The research includes the biology of aging and cancer, the impact of aging on cancer treatment, the quality of survivorship, symptom 

control, and disease-specific studies. 

Biology of Aging and Cancer 

Older patients differ from younger cancer patients 

in susceptibility to disease progression and 

response to treatment. The underlying mechanisms of cancer and aging overlap in the study of 

tumor initiation, progression, and maintenance. 

Studies to better identify the molecular alterations 

in carcinogenesis related to the aging process 

intersect a number of NCI priority areas. 

■ Genes and the Environment studies examine 

genetic changes, environmental influences, and 

host factors such as oxidant stress and cell 

death that may alter tumor progression in the 

aging patient. 

■	 Signatures of Cancer studies focus on the 

interaction of normal aging cells and cancer 

cells within the tumor microenvironment, differences in the manifestation of cancer types in 

older and younger patients, cellular and molecular characteristics that distinguish between 

46 The Nation’s Investment in Cancer Research 
those patients who could benefit from aggressive therapy and those who could be spared 

further therapy, and molecular alterations in 

carcinogenesis that are related to aging cells. 

■	 Cancer Imaging studies have led to an 

expanding array of diagnostic procedures such 

as the use of magnetic resonance probes, radiopharmaceuticals, and optical probes to reduce 

cancer treatment side effects and optimize 

recovery for older patients. 

■	 Quality of Cancer Care studies link the NCI 

SEER cancer registry to Medicare and other 

insurance data to assess the quality of cancer 

care and survivorship for older patients, early 

and late effects of treatment, occurrence of 

multiple primary tumors, and methodology for 

assessment and reporting. 

Improving Cancer Outcomes, 

Survivorship, and Symptom Control 

for the Aging 

We know that current healthcare practices frequently fall short of providing the best available 

early detection, treatment protocols, and quality 

care that older patients deserve. Studies show that 

older people are less likely to be screened for 

prevalent cancers such as breast, colorectal, and 

cervical disease. Older patients receive care for 

symptom control less frequently because of inadequate standards of care. For example, a 1998 study 

of cancer patients in nursing homes found that 

26 percent of patients with daily pain received no 

analgesics. A number of NCI-supported studies 

focus on issues of cancer treatment and care for 

older people. 

■	 The National Clinical Trials Program works 

to increase the accrual of people 65 and older to 

early trials through NCI Cooperative Groups 

and develops trials that are specifically 

designed for older cancer patients. Trials for 

new agents and toxicology models include 

efficacy and tolerance evaluations in the aging. 

Another important area for evaluation is 

radiation therapy in the older patient, including 

trials for tolerance to conventional and combined modality therapy as well as assessment 

of novel radiation with the potential for 

treatments that are faster and less morbid. 

■	 Quality of Cancer Care studies focus on 

developing guidelines for treatment decisions 

that assess co-morbid conditions and the limited functional reserve of the older person. 

Researchers are investigating the effects of 

multiple health problems on early detection, 

diagnosis, prognosis, and treatment of older 

cancer patients. Other studies test the efficacy 

of current methods of symptom management in 

older patients using evidence-based guidelines. 

■	 Survivorship studies identify potential shortand long-term medical effects induced by treatment such as susceptibility of the older patient to 

multiple primary tumors, anti-tumor drug alterations, and cancer recurrence. Future research 

will focus on developing methods to prevent or 

offset these problems in older persons. 

■	 Molecular Targets of Prevention and 

Treatment studies examine the human biology 

of cancer and aging that reveal which aspects of 

tumor biology and tumor growth vary by age. 

These investigations have the potential to provide information that could lead to tailored 

therapeutic approaches. 

Several recommendations for engaging NCI-supported Cancer Centers in pioneering research on 

issues faced by older cancer patients and their care 

givers came out of a June 2001 workshop jointly 

sponsored by NCI and NIA. For a full report on 

the workshop, go to nia.nih.gov/health/nianci. 

THE INTERF ACE OF AGING AND CANCER 

A Plan and Budget Proposal for Fiscal Year 2004 47

Studying the Impact of Colorectal 

Cancer on the Older Patient 

Colorectal cancer is third in cancer incidence 

and mortality in the United States. SEER data for 

1995-99 show that 70 percent of the incidence 

of colon and rectum tumors are in individuals 65 

years and older. Yet, there is a paucity of attention to older persons affected by these cancers. 

A much-needed knowledge base would include: 

■ Surveillance of persons at high risk 

■ Influence of concomitant age-related 

problems 

■ Gender and racial differences 

■ Pathogenesis of colorectal cancer 

■ Influence of coexisting diseases 

■ Criteria for older surgical candidates 

■ Modification of surgery procedures in older 

patients 

■ Preoperative assessment to assist surgeons 

in prognosis and treatment 
When cancer survivors and their loved ones ask me what 

NCI is doing to cure or prevent cancer, I tell them that we 

are finding many of the pieces of the cancer puzzle, and 

are learning what additional pieces to look for and 

where they probably fit. Cancer research has entered a 

whole new phase in how we identify and assemble the 

pieces. — Andrew C. von Eschenbach, M.D. 

Advancing Discovery and Its Application 

Part of the story is about how we are probing and discovering events at the molecular level and in 

the behavior of particular proteins. But molecules don’t smoke and proteins don’t neglect to wear sun 

protection, and genes don’t make the decision to join clinical trials of new treatments. 

So the story also includes research into lifestyle 

and behavioral factors and environmental exposures 

that so profoundly affect the burden of cancer. 

Once we more fully understand cancer-related 

molecular, cellular, microenvironment, behavioral, 

psychological, and social influences, we can 

develop more effective and less harmful approaches to cancer prevention, detection and diagnosis, 

treatment, and control. 

For Fiscal Year 2004, NCI’s scientific priority areas 

to accelerate the pace of research and its application include Extraordinary Opportunities for 

Investment in Genes and the Environment, Signatures 

of the Cancer Cell and Its Microenvironment, Molecular


Targets of Prevention and Treatment, Cancer Imaging


and Molecular Sensing, and Cancer Communications.


Increased investment in these areas is at the core 


of our ability to:


■ Understand the causes, risks, detection, 


diagnosis, and treatment of cancer and how to 

communicate this information effectively to all 

populations. 

■ Develop interventions based on these scientific 

insights. 

■ Ensure dissemination of interventions to all 

who need care. 

FY 2004 Increase Request for Advancing Discovery 

(dollars in thousands) 

Genes and the Environment $ 

Signatures of the Cancer Cell 

& Its Microenvironment $ 

Molecular Targets $ 

Imaging & Molecular Sensing $ 

Cancer Communications $ 

Total $266,250 

Signatures of the 

Cancer Cell & Its 

Microenvironment 

15% 

Molecular Targets 

21% 

Imaging & Molecular Sensing 

30% 

48 The Nation’s Investment in Cancer Research 

Genes and the 

Environment 19% 

Cancer 

Communications 

15% 

51,800 

41,200 

54,800 

78,700 

39,750 
Extraordinary Opportunity for Investment 

Genes and the Environment 

The Opportunity 

The debate over nature vs. nurture is as old as 

scientific inquiry itself. Is it a particular characteristic 

passed from one generation to another, or is it 

imposed by the world into which the individual is 

born? Especially with respect to cancer, that question has become far more difficult, because we now 

know that elements in the environment or a person’s 

lifestyle can damage genes, and we are finding that 

some genes seem to require certain conditions to 

give rise to cancer, while others virtually guarantee 

its occurrence. We have been able to identify some 

of the human genes that make people susceptible 

to cancer, to apply increasingly sophisticated 

molecular technologies to analyze genetic changes, 

and to examine the relationship between disease 

development and individual genetic profiles. 

We have learned about a variety of carcinogenic 

environmental factors, including pollutants in air, 

water, and soil; components of food, tobacco, alcohol, 

and drugs; sunlight and other forms of radiation; and 

infectious agents. 

Early efforts to discover how genes and environmental factors interact to cause cancer are showing promise but also highlight the complexity of the puzzle. 

Some genes have proven to be so powerful that their 

presence in an individual makes cancer highly predictable. For example, carriers of the gene for 

Familial Adenomatous Polyposis are almost certain 

to develop colon cancer. Mutations in the susceptibility genes BRCA1 and BRCA2 are risk factors for 

breast cancer that may arise from a combination of 

factors. Similarly, some environmental exposures, 

such as tobacco use, can be strong, but not certain, 

predictors of cancer. 

We want to learn how certain environmental 

exposures increase the cancer risk for genetically 

susceptible subgroups and uncover elements of the 

GOAL 

Discover genetic, environmental, and lifestyle 

factors and their interactions that define cancer 

risk and inform strategies 

for cancer control. 

gene-environment interaction that can lead to tangible improvements in our ability to prevent, detect, 

and control cancer. Once we can define the cancer 

risks associated with specific environmental and 

genetic factors and their interactions, we can then 

develop new individual and public health strategies to 

avoid adverse exposures, check genetic susceptibility 

earlier, and identify appropriate interventions and 

precautions for people at high risk. 

To make progress in this area, NCI needs to develop 

new ways to study cancer susceptibility genes, environmental exposures, and their interactions and to 

maximize the availability and use of large amounts 

of population data, biospecimens, laboratory models, 

and other resources. Large-scale studies, like the 

cohort consortium described below, with new levels of 

interdisciplinary cooperation and innovation from the 

cancer community will be needed to achieve tangible 

improvements in clinical practice and public health. 

Progress in Pursuit of Our Goal 

The NCI is pursuing research opportunities in several


growth areas to better understand cancer-related


genes, environmental and lifestyle factors, and their


interactions.1


Building Capacity through 


Large-Scale Collaborations


NCI is continuing to build the Cohort Consortium


to address the need for large-scale collaborations in


genetic epidemiology to unlock the full potential of


new discoveries in genomics. This consortium is


comprised of well established investigators who, indi­


vidually, had initiated over 15 separate prospective


studies of large population groups. Working together,


the Consortium will pool high quality environmental


exposure data along with information from biologic


specimens suitable for genetic analysis from over


700,000 participants. One group within the


49 ADV ANCING DISCOVER Y AND ITS APPLICA TION 

1 See the progress report and plan for research on tobacco and tobacco-related cancers on pages 94-98. 

A Plan and Budget Proposal for Fiscal Year 2004 
50 The Nation’s Investment in Cancer Research 

The Plan 

Genes and the Environment 

GOAL 

Discover those genetic, environmental, and lifestyle factors and their interactions that 

define cancer risk and that can inform the development of new strategies for prevention, 

early detection, and treatment. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Identify new environmental risk factors and susceptibility genes $13.00 M 

and determine their interactions in cancer causation. 

■ Utilize the unique advantages of the Cohort Consortium to investigate exogenous and 

endogenous4 exposures best studied in large populations and their interactions with 

susceptibility genes. 

— Support developmental studies based on the Consortium’s gene-environment study 

of breast and prostate cancers to determine the value of adding studies of other 

common cancer sites. 

— Expand the number of participants, population diversity, and types of biospecimens 

involved in these studies. 

■ Support the Case-Control Consortium to fully investigate gene-environment interactions 

for specific types of cancer. Initiate large population-based and hospital-based studies to 

develop comprehensive data and specimen resources by cancer site. 

■ Continue improving the infrastructures needed for large, collaborative human population 

studies with biospecimen components. 

— Maximize the efficiency and cost effectiveness of specimen collection, processing, 

storage techniques, and high-throughput assays for human population studies. 

— Enhance the capacity of informatics systems developed to capture, store, analyze, 

and integrate the massive amount of information generated by these studies. 

■ Support studies to determine the contribution of inflammation, injury, and infectious 

agents to the genesis of lung cancer, a need identified by the Lung Cancer Progress Review Group. 

2. Develop new ways to assess and measure environmental exposures $ 5.00 M 

for use in population studies. 

■ Continue expanding the Innovative Molecular Analysis Technologies Program to develop 

new non-invasive techniques for collecting and analyzing genes and gene products in very 

small biologic samples. 

■ Continue support for applying and validating measures of the cumulative cellular, genetic, 

and molecular effects of environmental exposure through funding supplements for ongoing 

research programs. 

4 An exogenous exposure originates from outside the body. . 

$2.00 M 

$2.00 M 

$5.00 M 

$2.00 M 

$2.00 M 

$2.00 M 

$3.00 M 

An endogenous exposure originates from within the body
ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 51

3. Identify cancer predisposing genes in high-risk families and $ 9.00 M 

investigate how other genes and environmental factors modify 

expression of these genes. 

■ Fund new consortia to identify susceptibility genes that remain to be discovered as well 

as other genetic and environmental modifiers of risk. $5.00 M 

■ Support interdisciplinary studies for gene discovery and characterization in new 

collaborative family registry groups. 

■ Support collection of fresh frozen tumor tissue and other biospecimens from cancer 

prone families for microarray based molecular signature analyses. 

4. Develop tools for the study of gene and environment interactions $ 3.00 M 

in human populations. 

■ Extend the Genetic Annotation Initiative to identify new gene variants and explore 

various molecular applications. 

■ Support the breast, colon, prostate, and pancreatic cancer comparative genetics work 

groups employing mouse models to help localize cancer susceptibility genes in humans 

and determine their function. 

5. Support collaborative studies of high-risk individuals to address $19.00 M 

the clinical, behavioral, and societal issues associated with 

cancer susceptibility. 

■ Sustain the Cancer Genetics Network as a resource for studies of clinical care for 

early detection, diagnosis, and treatment of genetically high-risk individuals, including 

those from minority and underserved populations. 

■ Expand support for studies in cancer genetics that examine psychosocial responses 

to cancer risk communication to inform the development of effective educational 

strategies and resources for patients, providers, and the public. 

■ Support research on the role of genetic factors and their interactions with 

physiologic and/or psychosocial factors among survivors of cancer. 

■ Refine cancer risk prediction methods/models to integrate genetic and environmental 

determinants of cancer. ge genetics based and environmental models. Refine 

models that predict risk and other outcomes among diverse populations. 

■ Collaborate with the Centers for Disease Control and Prevention Genomics and 

Public Health Centers to improve understanding of the value of family history 

in predicting the risk of cancer and translating this information into clinical practice 

and public health programs. 

Management and Support $ 2.80 M 

Total $51.80 M 

$2.00 M 

$2.00 M 

$3.00 M 

$11.00 M 

$4.00 M 

$2.00 M 

Mer

$1.00 M 

$1.00 M 
Consortium has developed a truly novel four-year 

collaborative study to identify critical gene-environment interactions in endogenous hormone pathways 

for over 7,000 cases each of breast and prostate cancer. A second group is pooling data for less common 

cancers, such as pancreatic cancers. 

The Case-Control Consortium is also investigating genetic and environmental determinants of cancer. For non-Hodgkin’s lymphoma, several investigators who have completed individual studies and collected biologic specimens, are formulating a combined study to give them the statistical power 

to uncover key gene-environment interactions. 

A second group of investigators, members of the 

NCI-supported HMO Cancer Research 

Network, is pooling its resources to develop the 

largest case-control study to date of pancreatic 

cancer. These researchers will employ “real time” 

electronic reporting of pathology, laboratory, radiology, and outpatient physician visit findings, resulting 

in the rapid identification of pancreatic cancer within ten working days. The purpose of this study is to 

develop a better understanding of risk factors for 

sporadic and familial pancreatic cancer and ultimately to use this knowledge for earlier detection and 

prevention. 

Assessing and Measuring 

Environmental Exposures 

Few population studies have investigated the question of whether environmental endocrine disruptors2 

have a role in adverse health effects, including 

cancer in humans. NCI is collaborating with the 

National Institute for Occupational Safety and 

Health, the Environmental Protection Agency, and 

the National Institute of Environmental Health 

Sciences to study organochlorine pesticides and 

polychlorinated biphenyls (PCBs) and their 

possible association with testicular and breast cancer 

risk. Researchers are following groups of infants 

born to mothers exposed to very high versus low 

(background) levels of PCBs through childhood and 

adolescence. The study provides a unique mechanism to assess whether early life exposures are critical in the eventual occurrence of cancer. 

NCI is funding 12 grants for geographic based 

research in cancer control and epidemiology. 

Half of these projects will apply innovative methods 

for assessing difficult to measure environmental 

exposures. One such innovation will use satellite 

imagery to estimate potential exposure to agricultural pesticides. The other grants will be used to develop methods and software to detect geographic patterns and clusters of cancer rates and to explore associations with environmental, sociodemographic, and 

access to care factors. 

The recently completed Observing Protein and 

Energy Nutrition Study assessed the measurement error inherent to studies in which patients 

must complete questionnaires or surveys to report 

their dietary intake. Investigators conducting this 

study, the largest ever of its kind, are comparing 

self-reported dietary intake data from 484 men and 

women with biomarkers that will reflect the actual 

diet of the patient. The results of the study will give 

us a better grasp of the reporting error so that we can 

more accurately interpret the findings of self-report 

dietary studies. 

Molecular profiling using innovative microtechnologies may be used to examine chromosome 

alterations and changes in protein levels following 

exposures to various environmental toxins that correlate with the appearance of cancer. For example: 

■ Scientists have found that changes in the 

levels of particular proteins (those whose 

genes may be altered by the biochemical 

process of methylation) have been associated 

with the development of cancer. NCI-funded 

molecular micro-technology research may permit 

identification of new environmental exposures 

that change the number of these important proteins in tissues. 

■	 Chromosome alterations in cancers are common 

and complex and often difficult to assess. New 

molecular technologies may be used to rapidly 

identify changes in chromosomes after exposure 

to environmental chemicals. 

Discovering and Characterizing 


Cancer Predisposing Genes 


The Breast, Ovarian and Colorectal Cancer


Family Registries will expand 1) the epidemiologic


and clinical follow-up of current participating high-


risk families; 2) the molecular characterization of


known colorectal, breast, and ovarian cancer 


susceptibility genes; and 3) the exploration of DNA


52 

2 Endocrine disruptors are synthetic or naturally occurring chemicals that affect the balance of hormonal functions. 

The Nation’s Investment in Cancer Research 
Behavioral Factors and the Risk of Cancer 

A number of studies have examined the relationship between cancer and a range of behavioral or lifestyle


factors such as tobacco use, diet, physical activity, and alcohol consumption. Some researchers estimate


that as many as 50 to 75 percent of cancer deaths in the United States are caused by behaviors or condi­


tions that can be altered. 


■ Cigarette smoking is the most preventable cause of death in the United States. It leads to nearly one-


third of the nation’s cancer deaths and is the major cause of lung cancer incidence and mortality. Tobacco 

use can also cause cancers of the larynx, mouth, esophagus, pharynx, and bladder, and it plays a role in 

cancers of the pancreas, kidney, and cervix. 

■	 Obesity increases the risk for several cancers including colon cancer, post-menopausal breast cancer, 

endometrial cancer, gastric cardia, and adenocarcinoma of the esophagus. People whose diets are rich in 

fruits and vegetables have a lower risk of getting cancers of the lung, mouth, pharynx, stomach, and colon. 

■	 Sedentary lifestyle is a risk factor for colon and breast cancer, and physical activity has been linked to 

decreased incidence of cancer, including a 50 percent lower risk of getting colon cancer as well as to 

improved quality of life and recovery for cancer patients. 

■	 High alcohol intake increases the risk of cancers of the mouth, esophagus, pharynx, larynx, and liver 

in men and women, and breast cancer in women. 

Choosing healthy behaviors such as not smoking, maintaining a healthy weight, being physically active, eating 

a low-fat diet rich in fruits and vegetables, and avoiding too much alcohol can help to reduce cancer risk. 

methylation and non-methylation related mismatch


repair mechanisms and their relationship to cancer


susceptibility. Studies will continue in breast, ovarian,


and colon cancer to search for new susceptibility or 


modifier genes; to better understand the interactions 


of genetic markers with dietary and hormonal factors;


and to develop new models for cancer risk prediction.


Family registries and collaborative groups are


identifying susceptibility genes for prostate cancer 


as well as other familial cancer syndromes and 


discovering mutations of known genes for cancer


site-specific susceptibility. NCI is also supporting


new groups of investigators to use large registries 


of cancer prone families. For example, a large 


international genetic epidemiology consortium is


studying melanoma.


Developing Tools for Gene 


Discovery and Characterization 


NCI is developing a high throughput Core


Genotyping Facility (CGF) capable of performing


40,000 genotypes every six weeks. The work will


expand to 100,000 genotypes with the installation of


an advanced Laboratory Information Management


System. The CGF program has established partner-


ships with the National Human Genome Research


Institute and several academic and commercial 


centers and is providing genomics support for the


first Cohort Consortium study, described above. 


The Centers for Disease Control and Prevention are 

funding three Genomics and Public Health 

Centers to develop methodologic standards specific 

to the collection and reporting of data from NCIbased population genetics research. This interagency 

collaboration is designed to more effectively move 

research results into clinical practice and public health. 

The Gail Model, developed at NCI, is a statistical tool 

to help estimate a woman’s risk of breast cancer based 

on a number of predisposing factors. A study of the 

reliability of mammographic densities was completed 

recently, and this characteristic has been found to be 

reliable enough to be formally included in the model. 

Supporting Intervention Trials and 

Translational Research on Inherited 

Susceptibility 

The Cancer Genetics Network (CGN) is a major 

NCI-supported infrastructure for studies of persons 

at high risk of cancer and for related translational 

research. CGN pilot studies combine existing and 

prospectively collected data to discover potentially 

important gene-environment interactions. The 

network collectively holds epidemiologic data on 

participants consistent with data collected by other 

NCI-supported consortia and registries allowing the 

information to be used either independently or in 

combination with other groups to explore geneenvironment interactions. 

A Plan and Budget Proposal for Fiscal Year 2004 

ADV ANCING DISCOVER Y AND ITS APPLICA TION 

53 
54 The Nation’s Investment in Cancer Research 

Genes and Proteins: Profiles of Hope 

Spotlight on Research 

With advances in artificial intelligence and laboratory technology, cancer researchers are moving from 

studying a limited number of genes and proteins at a time to studying complex patterns of these 

molecules, using gene expression array (GEA) and proteomic technology. These patterns of genes 

and proteins can be displayed as easy-to-read, computer-generated tumor profiles that 

clinicians may one day use to: 

■ Diagnose cancer earlier than is 

now possible, perhaps with a 

simple blood test. 

■ Identify molecular targets 

for cancer prevention and 

treatment. 

■ Develop individualized therapies using targeted treatments. 

■ Monitor and predict response 

to therapy. 

Recent advances in tumor profiling 

are pivotal and include the following: 

■ The Lymphoma/Leukemia 

Molecular Profiling Project, a 

consortium of researchers associated with the NCI Director’s 

Challenge research initiative, 

are using GEA to predict clinical outcome of diffuse large-B 

cell lymphoma patients. 

These scientists are also 

researching tumor profiles 

of other lymphomas with the 

goal of classifying human lymphomas according to differing 

molecular features that can be 

used to select the best possible 

therapy for each subtype of this 

disease. 

■ NCI-supported researchers are 

using GEA to discriminate 

between subtypes of acute 

lymphoblastic leukemia 

(ALL). One rapid test yields 

diagnostic information that 

ordinarily takes weeks to gather. 

ALL tumor profiling also 

appears to be more accurate 

and information rich than traditional diagnostic methods, 

even identifying patients at 

greatest risk for relapse or secondary cancers. Similar tumor 

profiles are being developed 

for subtypes of lung cancers. 

■ Researchers in the Clinical 

Proteomics Program, recently 

launched jointly by NCI 

and the Food and Drug 

Administration, have developed a prototype blood test for 

the early detection of ovarian 

cancer. In preliminary clinical 

trials, the investigators correctly classified 100 percent of 

women known to have this 

cancer, and 97 percent of those 

known to be cancer-free. 

If successfully refined, this 

blood test will be invaluable 

for detecting this highly invasive disease in its earliest 

stages, when it can be successfully treated. Similar blood 

tests are being developed for 

prostate,1 breast, and lung 

cancers. 

1 See also page 9. 

Researchers used gene expression 

array to generate this tumor profile 

that discriminates between three 

subtypes of diffuse large-B-cell 

lymphoma (DLBCL). Each row represents a single gene. Each column 

shows the DLBCL expression profile 

from a single patient. If a gene is 

over active, its square shows up red. 

Less active genes show up green. 

It is the overall pattern of expression 

for each patient that can identify 

the disease sub-type and provide 

valuable prognostic information. 

0.25 0.50 1.00 2.00 4.00 

Relative Level of Expression 

Gene 

Germinal center B cell-like Type 3 Activated B cell-like

Subgroup of Diffuse Large B-cell Lymphoma 

A-myb 

LMO2 

Jnk3 

CD10 

BCL-6 

Cyclin D2 

IRF-4 

Flip 

CD44 
Extraordinary Opportunity for Investment GOAL 

Accelerate our progress in understanding 

the dynamic interaction between cancer 

cells and their microenvironment and 

our application of this knowledge to 

the detection, diagnosis, prevention, 

treatment, and control of all cancers. 

Signatures of the Cancer Cell and Its Microenvironment 

The Opportunity 

Thirty years ago, cancer was a poorly understood 

and usually deadly disease. Today, we have a far 

better understanding of how cancer develops and 

progresses within the human body. Over the past 

three decades, scientists have determined that a cell 

becomes malignant as a result of changes to its 

genetic material and that accompanying biological 

characteristics of the cell also change. These 

changes are unique molecular “signatures” and 

serve as signals of the presence of cancer. This more 

robust understanding of the genetic alterations that 

occur within a cancer cell has changed the course of 

cancer research and has fueled new approaches to 

prevention, detection, diagnosis, and treatment. 

However, the cancer cell is only part of the story in 

cancer development. As a cancer cell grows within 

the elaborate architecture of the body’s tissues and 

organs, it interacts with its surrounding environment. Mounting evidence now suggests that a 

dynamic interaction occurs between the cancer cell 

and its local and systemic microenvironment, with 

each profoundly influencing the behavior of the 

other. This “tumor microenvironment,” is populated with a variety of different cell types, is rich in 

growth factors and enzymes, and includes parts of 

the blood and lymphatic systems. It conrtibutes to 

some of the most destructive characteristics of cancer cells and permits a tumor to grow and spread. 

The microenvironment can also influence the access 

of therapeutic agents to tumor cells, the body’s processing of treatment agents, and the development of 

resistance to cancer treatments. Although the cells 

in the microenvironment may not be genetically 

altered, their behavior can be changed through 

interactions with tumor cells. Physicians now realize 

that they confront a tumor entity that consists of 

malignant cells combined with their host tumor 

environment when treating a cancer patient. The 

cancer cells and their surrounding environment both 

need to be fully characterized in order to understand how cancer grows in the body, and both need 

to be considered when developing new interventions to fight it. 

Six years ago, NCI established the “Defining 

the Signatures of Cancer Cells” Extraordinary 

Opportunity to promote research aimed at identifying and characterizing the full compendium of signature changes that occur within cancer cells. Now 

we are expanding our efforts to consider how the 

interaction of the cancer cell and microenvironment 

permits, and even encourages, tumor development. 

Scientists pursuing this promising new scientific 

opportunity will read not only the signatures of cancer cells but also signatures of seemingly normal 

cells within the tumor microenvironment, and signatures that reflect changes that occur as cancer cells 

interact with the host microenvironment. NCI’s 

long-range goal is to extend signatures research to 

characterize the interaction among a tumor, its 

microenvironment, and the entire body. All of these 

signatures of cancer provide important clues for 

understanding cancer development, detection, diagnosis, and prognosis and are potential targets for preventive or therapeutic interventions. 

Progress in Pursuit of Our Goal 

Through a variety of ambitious initiatives, scientists 

studying the signatures of cancer are making important progress in identifying and characterizing both 

the signatures of premalignant and malignant cells 

as well as cells within the tumor microenvironment 

and validating these unique signatures as markers 

for early detection and diagnosis. 

The Cancer Genome Anatomy Project (CGAP), 

launched six years ago, is a critical vehicle for 

coordinating data and reagents that will support 

advances in molecular detection and diagnosis. The 

central goal of this project is to provide a complete 

picture of all the major molecular changes that occur 

ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 55
56 The Nation’s Investment in Cancer Research 

The Plan 

Signatures of the Cancer Cell and Its Microenvironment 

GOAL 

Accelerate our progress in understanding the dynamic interaction between cancer 

cells and their microenvironment and our application of this knowledge to the 

detection, diagnosis, prevention, treatment, and control of all cancers. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Define the molecular signatures of cells in the cancer microenviron- $10.00 M 

ment at various points during initiation and progression of cancer. 

Compare the molecular signatures of stromal and cancer cells during 

development and aging. 

■ Initiate a Consortium for Microenvironment of Tumors to define the molecular 

signatures of cancer cells and cells in the microenvironment. Establish a national 

core facility to facilitate the analysis of normal and cancerous cell samples for 

signature profiling studies. 

■ Develop a database of the molecular signature profiles of cells in the microenvironment 

and make these data readily available to the research community. 

■ Expand the Unconventional Innovations Program (UIP) to permit an increased focus 

on nanoparticles, molecular beacons, and high-resolution sensors and their use in cancer 

signature detection, targeting, and treatment. 

■ Expand the Innovative Molecular Analysis Technologies Program (IMAT) to enable 

development of micro- and nanotechnology tools to detect molecular signatures of 

cancer and surrounding cells. 

IMAT technology into tools that can be used in clinical practice. 

2. Define the dynamic communications among cancer cells, surrounding $ 7.00 M 

cells, and immune cells that control or promote tumor growth. 

Characterize the interaction between the immune system and the 

cancer cell during cancer initiation and progression. 

■ Fund studies focused on identifying the factors used by cancer cells to activate cells 

in the tumor microenvironment, which in turn support tumor growth and 

progression. 

■ Support studies to identify the origin of the cells and factors that comprise the 

tumor microenvironment. 

■ Develop organotypic culture systems that accurately model the interaction between 

the cancer cell and the tumor microenvironment in living systems. 

systems readily accessible to the research community. 

■ Develop technologies to enable researchers to assemble selected cell populations 

into tissues and engraft these “assembled” tissues into mice to observe and monitor 

the subsequent biological behavior of the grafted tissue. 

$4.00 M 

$1.00 M 

$2.00 M 

Facilitate collaborations that will assist in translating 

$3.00 M 

$1.50 M 

$1.50 M 

Make these 

$2.00 M 

$2.00 M 
ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 57

3. Support new approaches to provide the research community $ 6.00 M 

with rapid access to validated reagents. 

■ Establish a repository for antibodies, cell lines, animal models, and tissues that 

relate to cells in the microenvironment. 

■ Establish a database that includes comparisons of cellular interactions between 

cancer and surrounding cells in animal models to those in humans. 

■ Expand the Tissue Array Research Program (TARP) to include tissue microarrays 

of normal and cancerous tissues that are enriched for tissue from the tumor 

microenvironment. 

■ Expand the Clinical Proteomics Program to identify proteins and proteomic signatures 

in human cancer microdissected tissue samples (normal epithelium, premalignant 

lesions, adjacent tissue, and invasive cancer). 

4. Establish a spectrum of educational and communication initiatives $ 4.00 M 

involving scientists across various disciplines and with a broad range 

of expertise to enable progress in understanding the role of stromal 

cell interactions in cancer development. 

■ Encourage multi- and transdisciplinary investigations by establishing a new funding 

mechanism to allow co-investigators from different scientific fields to submit a 

collaborative grant application. 

■ Establish national trans-disciplinary training centers that will develop training 

curricula for students and established investigators and facilitate the 

development of novel studies in understanding the role of cellular interactions in 

cancer development. 

5. Apply knowledge of cellular interactions in cancer development, $12.00 M 

derived from profiling studies exploring cell-microenvironment 

interactions to create targeted interventions. 

■ Initiate a Rapid Access to Intervention Development program to efficiently 

develop new drugs that target cells in the microenvironment and move 

them into clinical use. 

■ Provide supplemental funding to NCI-funded investigators to develop 

new “targeted” reagents, including small molecules, RNAi, and antibodies. 

■ Fund functional and molecular imaging studies to visualize the physiologic, cellular, 

and molecular processes in living tissues. These studies should focus on (1) identifying 

the subtle and important early changes in the molecular biology of tumors and the 

microenvironment, as tumors become malignant and (2) monitoring the effects of 

therapy on tumor cells and the tumor microenvironment. 

Management and Support $ 2.20 M 

Total $41.20 M 

$1.00 M 

$1.00 M 

$2.00 M 

$2.00 M 

$2.00 M 

$2.00 M 

$2.00 M 

$5.00 M 

$5.00 M 
The Nation’s Investment in Cancer Research 

during cancer development. All CGAP data and 

resources are publicly accessible to the biomedical 

research community, enabling researchers to find 

“in silico”1 answers to biological questions in a 

fraction of the time it once took in the lab. 

■	 Through the Tumor Gene Index, CGAP has 

now generated more than 8 million gene tags 

(ESTs) from a wide variety of tumor types and 

their normal counterparts. Scientists are incorporating these ESTs into the design of microarrays 

and other technologies that will be used to classify tumors according to their molecular features. 

These molecular classification strategies hold 

the potential to improve cancer prevention, early 

detection, diagnosis, and treatment. 

■	 CGAP’s Cancer Chromosome Aberration 

Project was established to generate a genetic 

map that defines distinct chromosomal alterations associated with cancer. In 2002, investigators accomplished this initial goal, a milestone 

achievement in cancer research. 

■	 Full-length complimentary DNA clones are 

important tools for defining the sequence and 

function of genes expressed in human cells. 

Generating these clones, however, requires a 

considerable investment of an investigator’s time 

and funds. The NIH Mammalian Gene 

Collection, for which CGAP plays a leadership 

role, was created to generate individual full 

length human and mouse DNA clones for more 

rigorous study of individual genes, their protein 

products, and the role they play in human genes. 

The MGC has now identified potential fulllength clones for more than 20,000 human genes 

and 11,000 mouse genes. 

■	 CGAP’s Genetic Annotation Initiative focuses 

on exploring and applying technology to identify 

and characterize sequence variations, known as 

genetic polymorphisms, in genes important in cancer. A genetic polymorphism, which can affect a 

gene’s function, can arise when a mutation causes 

a change in even a single nucleotide of the DNA. 

Single nucleotide polymorphisms (SNPs) are 

important markers for cancer risk-related genes 

and also can be used to understand difference in 

vulnerability to cancer among individuals in a population. The CGAP SNP500 Cancer project, a 

new GAI effort, will sequence and make available 

to researchers 102 samples for known or newly 

discovered SNPs of immediate importance to 

molecular epidemiology studies in cancer. 

Innovations in laboratory technology and artificial 

intelligence are allowing scientists to move beyond 

studying genes or proteins one or two at a time, to 

studying the patterns (or profiles) of these molecules in normal, pre-cancerous, and cancerous cells. 

In 2001, NCI and the Food and Drug Administration 

launched the Clinical Proteomics Program (CPP) 

to apply advances in proteomics — the study of protein expression and function — directly to patient 

care. CPP investigators are pursuing a number of 

projects to achieve earlier detection of cancer 

through minimally invasive testing, individualized 

diagnosis and treatment strategies, determination 

of risks and benefits of treatments in the laboratory 

before use on patients, and enhanced understanding of tumors at the protein level, leading to molecular targeted therapies for cancer. 

NCI’s Biomedical Proteomics Program is supporting these efforts through its Mass Spectrometry 

Center. The center is a newly developed state-ofthe-art facility that employs several powerful new 

technologies to cleanly separate proteins and characterize their activities in cancer cells. Proteomic 

studies will also be aided by a technology recently 

developed by investigators funded through the 

Innovative Molecular Analysis Technologies 

program. This new technology combines the use of 

a laser (to release proteins directly from the surface 

of tissue sections) with mass spectrometry to 

accurately identify and localize proteins in cells 

and tissues. The technology, which has successfully 

imaged the location of proteins in tissue sections 

from human glioblastoma, prostate, and colon 

tumors, should provide new insights into molecular 

interactions within a cell. It also promises to be a 

valuable tool in the search for detection, diagnostic, 

and treatment markers. 

The Tissue Array Research Program (TARP), 

a collaborative effort between the National Human 

Genome Research Institute and NCI, is a valuable 

tool for testing interesting genes discovered in profiling studies. The TARP laboratory has produced 

more than 4,000 tissue microarray slides containing 

a variety of tumor and normal tissue samples. In a 

joint effort with the CPP, the TARP laboratory has 

also developed a cost-effective and user-friendly 

“cryo-array” platform that can be used to build 

arrays from very small tumor samples. 

58 

1 “In silico” techniques allow activities currently carried out in vitro or in vivo to be transferred to the computer. 

The Nation’s Investment in Cancer Research 
The Early Detection Research Network 

(EDRN) is a comprehensive, collaborative program 

that merges genetics with proteomics to provide a 

systematic view of how the molecular signatures of 

specific cancers can be used as unique, identifying 

markers. Through EDRN, NCI has created a 

national research infrastructure in which researchers 

from multiple institutions work together to identify, 

develop, and validate early detection markers. 

EDRN scientists have already discovered a number 

of novel biomarkers for breast, colon, lung, and 

prostate cancer and continue to pursue a variety of 

other promising investigations. 

NCI and EDRN scientists are jointly developing a 

proteomic profile for early detection of breast cancer 

based on the discovery of a protein profile in blood 

and breast fluid samples that distinguishes women 

without breast cancer from women with early, curable breast tumors. Researchers plan to test the protein profile defined by this study to determine its 

use as a marker for early detection of breast cancer. 

The same proteomics technology is also being tested for its applicability to ovarian, prostate, and lung 

cancer detection. In a preliminary trial of the technology to detect ovarian cancer, investigators were 

able to correctly identify ovarian cancer in all of 60 

women with the disease. Out of 66 patients known 

not to have cancer, 63 (or 97 percent) were correctly 

identified as cancer free. Although the accuracy of 

this test must be improved before it can be used to 

screen women in the general population, these are 

exceptionally promising preliminary results. 

Through the Director’s Challenge: Toward a 

Molecular Classification of Tumors initiative, 

investigators are developing profiles of molecular 

changes in human tumors using DNA, RNA, or protein-based analysis strategies to complement the 

current tumor classifications that are based on 

microscopic features. Three groups of Director’s 

Challenge investigators — using different experimental approaches — have identified expression 

profiles that differentiate early lung adenocarcinomas with a poor prognosis from adenocarcinomas 

that respond favorably to treatment. Although these 

tumors have different clinical behaviors, they cannot be distinguished from each other by their 

microscopic appearance. The ability to differentiate 

these tumors may help to distinguish between 

patients who can be cured by surgery alone from 

those who may benefit from more aggressive, or 

eventually, targeted interventions. The profiles may 

also reveal previously unknown molecular changes 

that can be tested as potential targets of new treatments. Director’s Challenge investigators have also 

reported new classification schemes for breast cancer and are working to develop new classification 

schemes in many other tumor sites. These results 

demonstrate the power of comprehensive molecular 

analyses to provide information that one day may 

guide a physician’s decision about the treatment 

course for individual patients. 

The Mouse Models of Human Cancers 

Consortium (MMHCC), a large initiative focused 

on developing and making available to researchers 

validated mouse models that mimic human cancers, 

is a vital part of cancer signatures research. With 

these models, scientists can identify and characterize cancer-associated molecular changes in complete 

organisms. Recently, several studies using 

MMHCC-developed prostate cancer mouse models 

demonstrated that growth factor signaling between 

the cancer and surrounding cells contributes to 

tumor progression. Based on this information, a 

group of researchers have engineered a new animal 

model lacking a specific growth factor in the tumor 

microenvironment to explore how growth factor loss 

may affect tumor progression. They also are studying mice engineered to over-express growth factors 

in either tumor or microenvironment cells to define 

the impact of these factors on tumor initiation. 

Finally, they are using mice with an intact signal 

system to design strategies to interrupt the signals 

as potential therapy. 

The Program for the Assessment of Clinical 

Cancer Tests (PACCT) facilitates the translation 

of new knowledge about cancer and new technologies into clinical practice. A Strategy Group, which 

guides the PACCT, has developed statistical 

designs for trials of markers that predict response to 

particular therapies. The Group has also developed 

an algorithm for developing new prognostic and 

predictive tests. Working groups will identify promising markers for node-negative breast and colon 

cancer and determine what steps need to be taken, 

according to the algorithm, to move these markers 

into clinical practice. In addition, a PACCT funding 

initiative has been developed to facilitate clinical 

trials to evaluate melanocyte tumor classification, 

molecular predictors of oral cancer, and the use of 

nipple aspirate to assess breast cancer risk. 

59 ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 
Extraordinary Opportunity for Investment 

Molecular Targets of Prevention 

and Treatment 

The Opportunity 

Recent advances in deciphering the human genome 

have launched an exciting new era in biomedical 

research with tremendous potential for cancer prevention, diagnosis, and treatment. New drugs can 

now be designed to target specific molecular features 

characteristic of cancer cells, including genetic 

mutations, factors causing changes in gene 

expression,1 structural changes in the proteins that 

are products of mutated genes, and alterations in 

signaling pathways.2 Molecularly targeted interventions result from the integration of multiple research 

disciplines and can be classified into five general 

molecularly targeted strategies that will guide 

future research. (See figure below.) 

Drugs developed using past paradigms attack both 

cancerous and healthy cells, often causing devastating short- and long-term side effects. Moreover, 

individual patient responses to conventional agents 

GOAL 

Facilitate the expanded exploration of the causes of cancer 

and the discovery and development of agents that specifically 

“target” these causes to prevent 

and treat cancer. 

vary, even in cases where cancers appear to be identical. Molecularly targeted therapies promise to be 

more selective, drastically reducing the incidence 

of side effects in patients. New diagnostic tools will 

permit clinicians to more precisely identify those 

patients who are most likely to benefit from a given 

therapeutic agent. Drugs developed to target one 

type of cancer are often found to be effective 

against other cancers as well. We foresee a day 

when the treatment for each patient’s cancer will be 

individualized based on the unique set of molecular 

characteristics expressed by his or her tumor. 

Progress in Pursuit of Our Goal 

NCI is advancing the identification of molecular 

targets and targeted drug discovery through a 

number of exciting initiatives. Several of these 

efforts address needs identified by Progress 

Review Groups, expert panels who assess research 

requirements for specific types of cancer. 

1 A gene is said to be “expressed” when the cell uses its genetic information to produce protein.


2 “Signaling pathways” are molecular interactions that begin when a cell receives a signal, such as a protein binding to a receptor, from outside of itself. 


60 The Nation’s Investment in Cancer Research 

Influence the cancer cell to re-regulate itself, 

or assume a more normal state. 

Turn on self-destruct pathways that cause 

a cancer cell to commit suicide. 

Stimulate the body’s immune system to 

reject the cancer. 

Prevent the cell from acquiring the capacity 

to repeatedly replicate itself. 

Interfere with a cell’s capacity to use 

surrounding tissue to support its growth — 

e.g., through angiogenesis. 

▼ 

▼ 

▼ 

Research Avenues for Molecular Targeting 8 

8 
Identifying and Validating 

Molecular Targets 

Through the Molecular Target Drug Discovery 

program, investigators identify and validate potential 

sites that can be exploited for cancer prevention and 

therapy, and develop tests to determine how effectively potential agents work on these targets. Other NCI 

programs support the development of resources for 

exploiting molecular targets. The Molecular Targets 

Laboratory capitalizes on the opportunities emerging 

from advances in genomics, molecular biology, combinatorial chemistry, informatics, and imaging, to create 

a resource of biological assays and compounds used to 

study molecular targets. The Mouse Models of 

Human Cancers Consortium is a collaborative 

program designed to derive and characterize mouse 

models of human cancers, and to generate resources, 

information, and methodologies to apply in cancer 

research. The Consortium expects to make available to 

researchers up to 30 new mouse models each year, and 

it is developing partnerships with pharmaceutical industry sponsors to facilitate the testing and evaluation of 

new compounds identified by consortium members.3 

Evaluating the Therapeutic 

Potential of Compounds 

NCI-supported chemists and biologists are collaborating to create libraries of synthetic, biological, 

and natural compounds to identify agents that can 

hit targets. The next step is to evaluate their therapeutic potential in molecular target assays. The 

National Cooperative Drug Discovery Groups 

program supports innovative, multi-disciplinary, 

parallel approaches for discovery of new anti-cancer 

treatments. Thirteen groups are progressing in a 

variety of areas. One group is developing novel 

vaccines targeting a receptor called Her2/neu that is 

over-expressed in up to 50 percent of breast cancers 

and is associated with metastatic disease and poor 

prognosis. In Biology-Chemistry Centers, interdisciplinary teams of scientists use a combination of 

chemical and biological techniques to create libraries 

of structurally diverse chemical compounds with 

potential anti-cancer effects. Using “smart” assays, 

scientists screen the compounds to identify those 

that will interact with cancer-specific molecular targets. 

The six teams funded through this initiative have 

screened hundreds of thousands of compounds for 

anti-cancer activity. Promising compounds include 

inhibitors of new blood vessel formation (angiogenesis), essential for tumor growth; a molecule that binds 

to growth factors and inhibits tumor growth; and a 

novel cell cycle inhibitor that could affect many cancers. Rapid Access to NCI Discovery Resources 

is a new program that expedites the development of 

drug research capabilities in academic institutions by 

assisting in the development of high-throughput laboratory assays to screen large numbers of promising 

chemicals. One recently funded project will target 

antibodies to angiogenin, an enzyme that can 

increase blood vessel growth in tumors. 

To expedite drug discovery, NCI is providing sample sets of more than 140,000 synthetic chemicals; 

80,000 natural products extracted from plants and 

marine organisms; and other biological materials to 

investigators who might have discovered potential 

targets. More than 60 research groups engaged in 

targeted cancer research have been supplied with 

these sets. Sample sets from the repository are helping NCI’s Chemistry and Biology Group with 

research on a novel cell cycle inhibitor. 

Translating Promising Target-Directed 

Compounds into Drugs for Human Use 

This is an exacting task that requires very specific, 

interrelated activities. NCI is supporting this critical 

arm of intervention development through a variety 

of initiatives. The Rapid Access to Prevention 

Intervention Development program expedites preclinical and early clinical drug development of investigational agents, with the potential to prevent, 

reverse, or delay carcinogenesis, by making the preclinical and early clinical drug development contract 

resources of NCI available to academic investigators. 

Through 17 currently funded projects, NCI supports 

clinical trials of mechanistically targeted agents to 

examine the effects of various chemopreventive 

agents on molecular targets. The Rapid Access to 

Intervention Development (RAID) program 

provides preclinical drug development resources to 

academic institutions in 62 current projects. Three 

interventions developed through RAID are now 

being tested in clinical trials. One intervention is a 

novel gene therapy approach that delivers a pair of 

therapeutic “suicide genes” to prostate tumors, rendering malignant cells sensitive to specific drugs and 

radiation. As many as six additional agents, targeting 

pediatric neuroblastoma, pancreatic cancer, and 

tumors expressing a variant epidermal growth factor 

receptor, will be in clinical trials by the end of FY 

2002.4 NCI’s Drug Development Group provides 

ADV ANCING DISCOVER Y AND ITS APPLICA TION 

61 

3 emice.nci.nih.gov 

4 dtp.nci.nih.gov/docs/raid/raid_index.html 

A Plan and Budget Proposal for Fiscal Year 2004 
62 The Nation’s Investment in Cancer Research 

The Plan 

Molecular Targets of Prevention and Treatment 

GOAL 

Facilitate the expanded exploration of the causes of cancer and the discovery and 

development of agents that specifically “target” these causes to prevent and treat cancer. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Identify, characterize, and validate the combinations of deregulated $ 6.00 M 

cellular proteins and pathways that cause cancer in pre-cancerous 

and cancerous cells. 

■ Through the Molecular Target Drug Discovery and other grant mechanisms, expand 

research to identify cellular targets and discover related anti-cancer agents. Provide 

screening assistance and informatics management. $6.00 M 

2. Determine the cancer-causing deregulated pathways that can be $ 7.00 M 

targeted by treatment or prevention agents. 

■ Amplify support for the Molecular Target Laboratory to bolster the systematic search 

for new preventive and therapeutic agents: 1) develop assays to identify possible 

treatments for cancer, and 2) acquire large libraries of natural and synthetic 

compounds. $5.00 M 

■ Support the Mouse Models of Human Cancers Consortium. $2.00 M 

3. Provide the infrastructure for researchers to develop assays to $16.00 M 

test large numbers of potential drugs against validated targets 

[e.g., deregulated proteins and pathways]. 

■ Expand support for the National Cooperative Drug Discovery Groups and encourage 

“partnering” arrangements with large and small pharmaceutical companies. $5.00 M 

■ Expand the availability of NCI discovery resources to academic laboratories through 

the Rapid Access to NCI Discovery Resources program. $1.00 M 

■ Support the creation of novel chemical compound libraries for molecular target assays 

through new Small Business Innovation Research initiatives. $4.00 M 

■ Develop a translational research program to closely link molecular imaging, cancer 

signatures, and molecular targets. These concurrent studies will couple the image to 

the biology to aid in credentialing new molecular targets. $3.00 M 

■ Develop screening assays to test candidates for probes and inhibitors of molecular targets 

and characterize and validate compounds that hit the targets through the intramural 

Molecular Targets Development Program. Support the isolation, purification, and 

characterization of individual components of natural product extracts. $1.00 M 

■ Develop a clinical proteomics initiative to use laser capture microdissection of human 

tissue specimens and to develop new laboratory tools for clinical proteomic applications 

in human cancer and drug toxicity detection. $2.00 M 

4. Facilitate the steps necessary to turn a target-specific lead $ 9.00 M 

compound into a clinical agent. 

■ Expand support for the Rapid Access to Intervention Development program. $3.00 M 

■ Increase funding to the Rapid Access to Prevention Intervention Development 

program to develop agents from the laboratory through clinical trials of efficacy. $1.00 M 
A Plan and Budget Proposal for Fiscal Year 2004 63

■ Support the development of novel methods of drug formulation and drug delivery 

through new Small Business Innovation Research initiatives. $2.00 M 

■ Expand assistance to small business drug research and development through the 

Flexible System to Advance Innovative Research program. $3.00 M 

5. Investigate the use of novel combinations of radiation therapy $ 

with molecular therapeutics. 

■ Support individual investigators and industry to develop treatment programs using 

new agents with radiation therapy. $0.50 M 

6. Fund Clinical Trials Networks that will take drug candidates into $ 

human trials and determine if the drug affects the intended target 

and the progression of the cancer. 

■ Widen support for the Interdisciplinary Research Teams for Molecular 

Target Assessment. $2.00 M 

7. Utilize current technologies to make the next generation of cancer $ 

vaccines more effective in inducing anti-cancer responses, either 

before or during the use of other therapies. Support vaccine 

development and clinical trials of new vaccines. 

■ Develop more potent vaccines by integrating various approaches and translating them 

into optimal therapies for human cancer. $1.50 M 

■ Generate specialized cell types, such as dendritic cells, for use as vaccines. $0.70 M 

■ Create animal models that both develop spontaneous tumors later in life, to allow time 

for appropriate vaccination protocols, and express tumor-associated antigens 

similar to those in humans. $0.30 M 

■ Establish laboratories to analyze new gene products for potential use in cancer 

vaccines and to develop methods to increase immunogenicity. $0.50 M 

■ Expedite the development of clinical trials to assess the efficacy of new vaccines for 

the treatment of colorectal, prostate, breast, lung, bladder, pancreatic, and head and 

neck carcinomas; myeloma, lymphoma, and melanoma; and other tumor types. 

— Develop new funding mechanisms to support clinical trials. $2.50 M 

— Obtain and make available samples of immune cells and tumor tissue from patients 

for immunoassay testing. $0.50 M 

■ Establish centralized immunoassay laboratories to analyze patient immune responses 

both prior to and during vaccine clinical trials. Supplement existing laboratories to 

develop immunoassays to select good candidates for vaccine therapy. $0.50 M 

■ Develop and conduct clinical trials to test the efficacy of using cancer vaccines in 

combination with existing therapies including chemotherapy, hormonal therapy, or 

local radiotherapy. $1.50 M 

■ Develop new surrogate markers of vaccine efficacy and tests revealing the presence 

of bloodborne tumor cells that express tumor antigen genes. $0.30 M 

Management and Support $ 

Total $54.80 M 

ADV ANCING DISCOVER Y AND ITS APPLICA TION 

0.50 M 

2.00 M 

8.30 M 

6.00 M 
support for academic and corporate-derived compounds when NCI is responsible for conducting and 

monitoring the drug’s clinical development. For 

more than 15 years, researchers have attempted to 

design cancer therapies to avoid toxicities associated 

with standard chemotherapeutic agents. BL22, an 

immunotoxin that specifically targets hairy cell 

leukemia (HCL), originated in an intramural NCI 

laboratory and was developed through NCI’s biologicals production facility. It is now showing promising 

results in a Phase I trial: 11 of 16 patients with 

chemotherapy-resistant HCL have shown complete 

remission, lasting up to 18 months, mostly without 

major side effects. The Flexible System to 

Advance Innovative Research provides funds to 

small businesses to develop cancer therapeutic and 

prevention agents from basic discovery to clinical trials. One of these grants supported development of 

an immune modulating agent called A-007, already 

in Phase I clinical trials. This agent has been 

approved for Phase II trials to test its efficacy in 

treating cervical cancer. The Radiation Modifier 

Evaluation Module program will serve individual 

investigators and industry in the design and development of treatment programs using novel molecular, biologic, and cytotoxic agents in conjunction 

with radiation therapy. This integration is a high priority of NCI’s Intramural Program because new anticancer agents may ultimately be used in combination with radiation therapy. 

Developing Clinical Trials Programs To 

Study New Molecular Target Agents 

As part of large-scale prevention trials, NCI supports 

supplemental studies and specimen repositories 

aimed at answering a variety of mechanistic and 

molecular questions. For example, in the Selenium 

and Vitamin E Cancer Prevention Trial, scientists will assess the molecular genetics of cancer risk 

and associations between diet and cancer. In the 

Breast Cancer Prevention Trial, the Study of 

Tamoxifen and Raloxifene focused on the estrogen receptor as a key to breast cancer risk. 

NCI is fostering teams of interdisciplinary scientists 

through the Interdisciplinary Research Teams 

for Molecular Target Assessment. These teams 

study critical biological processes to uncover high 

priority targets for cancer prevention or treatment 

and drug discovery. The first set of applications, 

focusing on angiogenesis, tumor proliferation, tumor 

vaccines, and structure of tumor chromosomes, was 

funded in 2001. 

Fostering Interdisciplinary Collaborations 

through NCI Intramural Programs 

NCI’s Center for Cancer Research, which 

coordinates all intramural basic and clinical research, 

expedites rapid and efficient translation of basic scientific advances into new tools, reagents, and molecularly targeted leads. Major priorities of the Center 

include fostering interdisciplinary collaborations 

between basic researchers and clinical investigators 

and training postdoctoral fellows to function in this 

new research environment. To this end, NCI has 

formed the Molecular Targets Faculty, composed 

of scientists from diverse laboratories and branches 

working together cooperatively as part of the intramural Molecular Targets Development Program. 

The Program also promotes collaborations with various academic and pharmaceutical partners and is 

designed to facilitate the discovery of compounds 

that can serve as probes for functional genomics, 

proteomics, molecular target validation, or as candidates for drug development. 

Recognizing the importance of anti-cancer vaccines 

in prevention and treatment, NCI has established 

the Center for Cancer Research Vaccine 

Initiative, a consortium of multidisciplinary scientists, consisting of expert clinicians and industrial 

representatives. This consortium has spearheaded 

the development of new, more sophisticated recombinant vaccines that are now in the clinic and others 

that will enter the clinic shortly.

5 The potential of 

proteomics to further cancer research is being 

exploited by two other programs. The Biomedical 

Proteomics Program provides NCI investigators 

with the most powerful analytical approaches available to further the understanding of the molecular 

mechanisms underlying carcinogenesis and tumor 

progression and works hand in hand with the NCI 

Clinical Proteomics Program to identify proteins 

and pathways important in human cancers. 

64 

5 See page 16 for more information on the Vaccine Initiative. 

The Nation’s Investment in Cancer Research 
Extraordinary Opportunity for Investment GOAL 

Accelerate discovery and development of 

imaging methods, biosensors, and minimally 

invasive image-guided therapies to predict 

clinical course and guide and predict 

response to interventions. 

Cancer Imaging and Molecular Sensing 

The Opportunity 

Over the last quarter century, investment in cancer 

imaging has dramatically improved the quality of 

patient care by making it possible to detect tumors 

much earlier when they are easier to treat and by 

permitting more precise therapy or surgery. New 

imaging techniques can be used to determine, in 

real time, if a tumor has invaded vital tissue, grown 

around blood vessels, or spread to distant organs. 

Imaging supports various tumor-destroying 

approaches (chemicals, radiation, gene therapy, heat, 

and cold) to minimize surgical trauma and damage to 

healthy tissue, shorten recovery time, and reduce 

healthcare costs. Molecular or “functional” imaging1 

of the physiological, cellular, or molecular processes 

in living tissue can sometimes allow physicians to 

monitor their patients’ progress and response to 

therapy without the need for biopsies. 

Indeed, more imaging resources are devoted to the 

study and treatment of cancer than to any other disease and, in many ways, the needs of cancer research 

and treatment drive the direction of imaging 

research. As we learn more about the molecular basis 

for cancer, this level of sustained investment in cancer imaging becomes even more necessary and productive. For example, micro-imaging technologies 

are needed to fully utilize the increasing number 

of mouse models of human cancer to uncover the 

genetic basis of specific tumors. We need to develop 

functional imaging to study how newly discovered 

defects in genes and proteins interact to cause cancer. Recent discoveries in cancer signature and 

molecular therapeutic research demand new ways to 

assess the effectiveness of molecularly targeted 

treatments in clinical trial settings. 

At the same time, we must invest in applying the 

new technologies emerging from the study of 

nanoscience2 that promise to give biomedical 

researchers and healthcare providers even more 

options for detecting and monitoring biologic events 

in cancer. Researchers are designing molecular 

biosensors to be injected into the bloodstream to 

seek out and destroy cancer cells. These biosensors, 

about 10,000 times smaller than the head of a pin, 

will also allow physicians to image the cancer and 

follow the patient’s response to therapy — all 

with minimal side effects and little disruption of 

healthy tissue. 

NCI has a unique opportunity to further improve 

cancer imaging and molecular sensing technologies 

to ensure earlier and more accurate diagnoses for 

cancer patients, reduce the number of invasive 

interventions, guide individualized therapies, and 

improve monitoring of patient response to treatment. With additional investment in research and 

development, significant advances in these areas 

will increasingly save and improve lives. 

Progress in Pursuit of Our Goal 

NCI’s investment in developing better imaging 

technologies for both cancer research and clinical 

practice are tangibly impacting patient’s lives. 

Developing Better Imaging 


Technologies and Techniques


NCI has played a major role in fostering functional


imaging through initiatives such as In Vivo Cellular


and Molecular Imaging Centers (ICMICs). With


five Centers established as of 2002, each ICMIC brings


together experts from diverse scientific and technologi­


cal backgrounds to conduct multidisciplinary research


on cellular and molecular imaging in cancer.


65 ADV ANCING DISCOVER Y AND ITS APPLICA TION 

1 Molecular imaging techniques do not actually reveal molecules themselves, but they detect signals that indicate the presence of biochemical activity and changes, 

such as cell growth or death. Thus, molecular imaging is often described as “functional,” because the processes being imaged are active and constantly changing. 2 Nanoscience is the study of objects and phenomena on extremely small scales. 

A Plan and Budget Proposal for Fiscal Year 2004 
66 The Nation’s Investment in Cancer Research 

The Plan 

Cancer Imaging and Molecular Sensing 

GOAL 

Stimulate and accelerate discovery and development of imaging methods and biosensors to 

identify the biological and molecular properties of precancerous or cancerous cells that will 

predict clinical course and response to interventions. Advance the development and 

implementation of minimally invasive image-guided therapies. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Expand the discovery, design, and development of novel imaging $34.80 M 

agents and devices. 

■ Establish two additional In Vivo Cellular and Molecular Imaging Centers (ICMICs) 

to foster multidisciplinary research in this area of study. $4.00 M 

■ Increase the number of imaging agents supported by the Development of Clinical 

Imaging Drugs and Enhancers program from three to five per year. $4.00 M 

■ Increase collaborations between Small Animal Imaging Resource Programs (SAIRPs) 

and other NCI programs such as the Mouse Models of Human Cancers Consortium 

(MMHCC). $2.00 M 

■ Provide 10 supplements to SAIRPs to upgrade to state-of-the-art 

imaging devices. $5.00 M 

■ Speed the development of imaging agents by funding supplements to grantees 

in a variety of NCI programs that perform research on molecular imaging. $2.00 M 

■ Fund research supplements to investigators to make their imaging discoveries such 

as contrast agents, assays, devices, and software available to others. Establish a repository 

of imaging agents for investigators at the National Cancer Institute at Frederick. $3.50 M 

■ Establish data banks of standardized digital image or spectroscopy data (such as virtual 

colonoscopy, digital mammography, digital chest imaging, and optical spectroscopy) 

associated with known clinical outcomes as a research resource. Expand the NCI-funded, 

publicly available, Molecular Imaging Database of imaging agents. $5.30 M 

■ Fund six to eight grants to develop and test image processing and analysis 

algorithms (artificial intelligence). $2.00 M 

■ Fund four grants (RFA) to stimulate the development of combined 

modality devices. $4.00 M 

■ Accelerate commercialization of imaging discoveries by fostering academic-industry 

collaborations with funding supplements similar to the National Science Foundation 

Grant Opportunities for Academic Liaison with Industry (GOALI) program. $1.50M 

■ Fund four grants to develop standardized image acquisition and image processing 

protocols for calculating quantitative endpoints for clinical trials. $1.50 M 

2. Increase clinical trials of imaging methods and technologies. $ 14.00 M 

■ Initiate clinical studies to evaluate: computed tomographic colonography 

(virtual colonoscopy) compared to endoscopic colonoscopy for early detection of colon 

cancer and polyps in a large multi-institutional setting; magnetic resonance (MR) 

spectroscopy for the early detection and assessment of prostate cancer; MR imaging 

and ultrasound for early detection of breast cancer; and positron emission tomography 

for monitoring tumor response to therapy. $10.00 M 
ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 67

■ Support correlative imaging studies, such as monitoring response to therapy, with 

10 funding supplements to Clinical Trials Cooperative Groups. $4.00 M 

■ Fund a workshop to talk with industrial and academic leaders about applying the 

latest imaging technology to lung cancer detection. 

3. Integrate molecular and functional imaging methods into $12.20 M 

therapeutic clinical trials. 

■ Increase the contract support for early clinical trials of imaging agents 

(safety and efficacy studies) from 6 to 10 trials per year. $2.00 M 

■ Provide imaging expertise to clinical trials by funding supplements or grants for 

10 to 15 imaging cores within NCI-funded Cancer Centers and support expert panels to 

develop consensus criteria for using imaging results as endpoints in clinical trials. $4.20 M 

■ Provide funding for dedicated imaging equipment (infrastructure) for clinical trials. $5.00 M 

■ Expand a contract program to validate imaging methodologies in pre-clinical testing 

of new drugs. $1.00 M 

4. Accelerate the development and clinical testing of image-guided $12.00 M 

interventions. 

■ Use 6 to 10 funding supplements to enhance programs such as the SPOREs for imageguided therapy research that emphasizes a problem-solving, organ-specific approach and 

promotes interactions between clinicians and bioengineers. $3.00 M 

■ Increase collaborations between the American College of Radiology Imaging Network 

and other NCI-funded Clinical Trials Cooperative Groups for testing promising, minimally 

invasive, image-guided interventions with 4 to 6 funding supplements. $2.00 M 

■ Support 6 grants to develop the tools and infrastructure to incorporate functional 

and molecular imaging into radiation therapy planning. $2.00 M 

■ Fund an initiative of 10 grants (RFA) to stimulate the development and systems 

integration of hardware and software tools and for image-guided delivery of therapies 

to solid tumors. $5.00 M 

5. Stimulate research on components and systems integration of devices $ 4.00 M 

for in vivo molecular sensing (biosensors). 

■ Fund 6 to 8 supplements to investigators in the Innovative Molecular Analysis 

Technology, Unconventional Innovation Program, or NCI-NASA collaboration to 

develop biosensors or components of biosensors for in vivo use. $2.00 M 

■ Promote research on biosensor systems integration by funding a Center for Biosensors in 

Oncology, based on the National Science Foundation Engineering Research Center 

model. $2.00 M 

Management and Support $ 1.70 M 

Total $78.70 M 
NCI is providing support for the planning of another 

14 potential ICMIC sites. For highlights of one 

ICMIC team effort, see the sidebar below. 

NCI’s Development of Clinical Imaging Drugs 

and Enhancers (DCIDE) program is continuing to 

foster the development of new imaging contrast 

agents and molecular probes to improve the 

diagnosis and treatment of cancer. By its second 

year, DCIDE will be developing as many as seven 

imaging agents or probes designed to measure blood 

vessel formation and cell death, evaluate cell growth, 

and enhance visualization of prostate and other cancers. 

Several of NCI’s Progress Review Groups have 

stressed the need for publicly available imaging 

databases to support optimal growth in imaging 

research and technology. The NCI-supported 

Molecular Imaging Database, expected to be 

released in 2002, will help researchers develop 

new imaging agents and help clinicians find existing 

agents for imaging specific cancers. 

By early 2003, NCI’s Lung Imaging Database 

Consortium will provide databanks of standardized 

digital image data from cancer patients, together 

with clinical outcome information, a resource much 

requested by researchers. 

Researchers of the Mouse Models of Human 

Cancers Consortium (MMHCC) are developing 

inventive imaging modalities for use in preclinical studies. One group is using MRI to learn 

how to deliver anti-tumor therapy to the brain using 

neural stem cells. Other researchers use a unique 

micro-computed tomography imaging (micro-CT) 

contrast agent to visualize metastatic tumors in the 

livers of mice with invasive colon cancer. This team


developed a second agent to track metastases in


other organs throughout the mouse.


Bringing Advances in 


Imaging to Cancer Care 


NCI is supporting clinical trial research to move


promising imaging advances from discovery and


development to clinical use. New cancer imaging


technologies and techniques are often evaluated


through one of NCI’s clinical trials cooperative


groups. These groups are networks of healthcare


professionals affiliated with medical schools, teach­


ing hospitals, and community-based cancer treat­


ment centers. For example, the American College


of Radiology Imaging Network (ACRIN) recently


completed a study to determine whether computed


tomography (CT) scanning — a technique some-


times known as “virtual colonoscopy” — is sufficiently


reliable for colon cancer screening to warrant further


study. Based on their promising results, a large-scale


trial will follow this study. 


Other ACRIN efforts are underway to determine: 


■	 Whether combined Magnetic Resonance 

Imaging (MRI) and Magnetic Resonance 

Spectroscopic Imaging can be used to accurately 

localize and diagnose prostate cancer. 

■ Whether CT scanning can be used to reliably 

measure tumor volume of supraglottic cancer. 

■ How the drug GleevecTM impacts the biology 

of Gastrointestinal Stromal Tumors (GIST). 

■ Whether CT or MRI can improve the pretreatment evaluation of invasive cervical cancer. 

68 The Nation’s Investment in Cancer Research 

Functional Imaging of Low Activity Genes by ICMIC Researchers 

For years, cancer researchers have been studying certain highly important, but low activity, genes in their work with 

animal models. The “activity” of a gene — usually measured by how much protein it is making — helps the scientist 

understand how the gene is affecting the biology of the cell. However, the protein levels of low activity genes are often 

too minute to measure. To overcome this difficulty, one team of In Vivo Cellular and Molecular Imaging Center (ICMIC) 

researchers, studying the gene for prostate specific antigen (PSA) in mice, recently developed a technique known as 

two-step transcriptional amplification (TSTA). s PSA gene so that it would 

produce a small amount of a special protein whenever the PSA gene was active. For the second step they added a 

separate gene that will produce large quantities of an easily measured fluorescent chemical, when in the presence of 

even small amounts of the special protein. Then, by measuring fluorescence, they determined the activity level of the 

PSA gene. The ICMIC researchers expect to develop the TSTA approach for study of a variety of low activity genes, 

adding to our understanding of a number of cancers and how to prevent, detect, and treat them. 

In the first step, they changed the mouse’
Nanoscience — New Opportunities for Detection, Monitoring, and Intervention 

Recent advances in understanding the molecular basis of cancer raise the possibility of diagnosing, 

treating, and monitoring cancer with increasingly specific, even individualized therapies. A number of 

researchers in the field of nanoscience have started to develop synthetic spheres of molecules that 

can seek out and examine cancer cells. These special spheres, referred to as nanoparticles because 

they are thousands of times smaller than a single cell, can carry a variety of specially designed molecular-sized attachments that allow them to act as a type of biosensor. These remarkable nanotechnology 

innovations can be designed to seek out, analyze, and treat cancer cells — all without harming healthy 

cells. NCI-supported researchers are developing such a biosensor to locate brain tumor cells and tag 

them for easy imaging. The biosensor can then be targeted with an external laser beam to activate a 

special chemical attachment designed to kill the cell. Other exciting projects in nanotechnology are 

taking shape in laboratories across the country. Although human testing is years away, with proper 

funding and interdisciplinary cooperation, scientists envision making significant progress in this field 

within 5 to 10 years. Ultimately, we look for a day when many cancer patients will be effectively diagnosed, treated, and monitored with a simple injection and non-invasive monitoring rather than with 

surgery, chemotherapy, radiation, or other conventional therapies. 

The Digital Mammography Imaging Screening 

Trial, another large-scale ACRIN trial, is comparing 

the diagnostic power of digital mammography to 

conventional, film-based mammography. Over 6,000 

women have enrolled at 18 locations across the 

United States, and another 10 sites will be added in 

2002. ACRIN is also helping to design and conduct 

the NCI-funded National Lung Screening Trial 

(NLST), which will determine the merit of spiral 

computed tomography (CT) for lung cancer detection compared to X-ray screening. NLST will utilize 

the infrastructure developed in the up-and-running 

Prostate, Lung, Colorectal, and Ovarian 

Cancer Screening Trial to enroll 50,000 current or 

former smokers for screening at 30 study sites 

throughout the United States. 

Other NCI-sponsored networks are also evaluating 

the use of imaging technologies. For example, the 

American College of Surgeons Oncology Group is 

determining the value of positron emission tomography, or PET, for lung cancer staging. In addition 

to supporting these and other large-scale clinical trials for imaging technologies, NCI is providing infrastructure to support early phase clinical testing of 

imaging agents and probes at various centers and 

NCI-supported programs around the country. 

NCI also recognizes the crucial place of partnerships 

to translate budding imaging technologies into practices that improve patient care. For example, NCI’s 

Novel Imaging Technologies program supports 

collaboration of academic scientists with 

industry and foreign institutes to create unique 

imaging technology. One team of NCI-funded 

investigators is developing the next generation of 

the PET/CT scanner for improved localization and 

evaluation of difficult-to-pinpoint cancers and therapeutic monitoring. 

Furthermore, NCI is working to integrate imaging 

into a broad cross section of cancer clinical 

trials as a way to make the trials more efficient. For 

example, NCI cooperative groups are working with 

the Cancer Therapy Evaluation Program, or CTEP, 

to identify how to use imaging as a biomarker or 

surrogate marker — perhaps instead of a biopsy — 

to demonstrate the effectiveness of a treatment. 

In April 2002, NCI held a workshop, “Role of 

Biological Imaging in Radiation Oncology.” 

Scientists identified the next steps needed to 

integrate functional and molecular imaging with 

radiation therapy to improve tumor control while 

minimizing damage to healthy tissues. 

69 ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 
Harnessing Apoptosis to Destroy Cancer Cells 

Story of Discovery 

In 1972, John Kerr, Andrew Wyllie, and Alistair Currie published a paper describing a little known and 

curious form of cell death that today is one of the most intensively studied topics in modern biology. 

They reported on programmed cell death, which they labeled “apoptosis,” noting that it was distinctly 

different from the long recognized cell death process known as necrosis. In necrosis, a cell ruptures, 

causing inflammatory cells to rush in to clear away the debris. 

70 The Nation’s Investment in Cancer Research 

Apoptosis, however, is clean and 

quick: a cell shrinks and is rapidly digested by neighboring 

cells. Although biologists have 

long known that apoptosis is 

important in embryogenesis, 

Kerr, Wyllie, and Currie were 

the first to observe that it occurs 

in mature cells. They also were 

the first to hypothesize that its 

failure contributes to a variety 

of diseases, including cancer. 

Unfortunately, this groundbreaking paper created little 

excitement in the scientific 

community until more than 

ten years later when Nobel 

prize winner H. Robert Horvitz 

used the microscopic roundworm, C. elegans to explore how 

a single fertilized egg develops 

into an adult organism. As he 

painstakingly followed each of 

the developing worm’s 1,090 

cells to their ultimate fate, he 

was surprised to see that 131 

cells died via apoptosis as the 

worm matured into adulthood. 

With this observation, he substantiated the prediction made 

by Kerr and his colleagues that 

apoptosis occurred beyond 

embryogenesis. By 1986, 

Horvitz determined that three 

genes were responsible for regulating apoptosis in C. elegans and 

demonstrated for the first time 

that this process is genetically 

programmed. Horvitz and his 

colleagues also determined that 

these genes are broadly conserved among plants and animals, indicating that apoptosis 

has been sustained through evolution and has a universally 

important biological function. 

These findings greatly energized apoptosis research. Over 

the next 15 years, scientists 

confirmed that apoptosis plays a 

central role in developing organisms by shaping neural and 

immune systems and molding 

tissue specificity, and in mature 

organisms by establishing a natural balance between cell death 

and renewal as it destroys excess, 

damaged, or abnormal cells. 

Additional studies have 

revealed that apoptosis occurs 

through two distinct cellular 

pathways, one of which is initiated by signals outside the cell, 

the other by signals from within. Both pathways converge 

inside the cell, turning on a central executioner family of proteins known as caspases. 

Caspases act as knives, cutting 

up proteins inside the cell and 

digesting the cell from within. 

Because caspases become activated early in apoptosis and 

irreversibly launch a cell’s death 

machinery, scientists sought 

their trigger. In 1996, Xiaodong 

Wang and colleagues discovered 

that caspases are activated by 

cytochrome c, a critical protein 

component of the mitochondria 

(the energy-producing structures of cells). With this finding, 

scientists began to study the 

mitochondria to determine how 

apoptosis functions in the cell, 

and malfunctions in disease. 

Connecting Failed 

Apoptosis and Cancer 

The link between apoptosis and 

cancer was not established until 

1988 when David Hockenbery 

and colleagues characterized the 

bcl-2 gene. Bcl-2 was first discovered in B cells (an immune 

cell) from patients with follicular lymphoma (an immune system cancer). Hockenbery determined that the normal bcl-2 is a 

suicide “brake” gene — it produces a protein that blocks 

apoptosis. In lymphoma 

patients, the abnormal form of 

the gene is overactive, causing 

the anti-apoptosis protein to be 

overproduced. Cancer develops 

as more and more B cells are 

generated and fail to die. 

This finding, a milestone in 

cancer research, revealed that 

increased cell division was not 

the only way that tumors could 

develop. Cells could also 

A muscle cell undergoing apoptosis. 
become potent promoters of 

tumor growth by avoiding programmed cell death. 

Throughout the 1990s, scientists gathered considerable information about bcl-2. They determined that increased bcl-2 protein production occurs in several 

cancers (B cell leukemias, lymphomas, colon and prostate cancers, and neuroblastoma) and is 

linked with poor disease outcome. In addition, overexpression of the bcl-2 gene may confer 

resistance to chemotherapeutic 

drugs. In 1997, scientists determined that the bcl-2 protein 

prevents apoptosis by blocking 

the release of cytochrome c from 

inside the mitochondria. 

Because resistance to the apoptosis-inducing effects of 

chemotherapy appears to develop from changes within the 

mitochondria of tumor cells, scientists now are working to 

develop a complete picture of 

how bcl-2 controls cytochrome c 

release so that they can improve 

the suicide-provoking effects of 

cancer treatments as well as 

thwart a cancer cell’s ability to 

evade these drugs. 

Although bcl-2 was the first 

component of the cell suicide 

mechanism to be identified, this 

dauntingly complicated process 

has many genetic controls. For 

example, the p53 protein, 

known as the guardian of the 

human genome, serves as an 

important tumor suppressor 

because it either blocks the cell 

division of a genetically damaged cell or triggers apoptosis 

by causing damage to the mitochondria and cytochrome c 

release. In 55 to 70 percent of 

human cancers, however, genetic mutations render the p53 protein deficient and cells with 

DNA damage can continue to 

accumulate. Loss of p53 function is associated with tumor 

aggressiveness and resistance to 

anti-cancer treatments. 

Evidence indicates that acquiring apoptosis resistance is a hallmark of most, and perhaps all 

types of cancer. As scientists 

learn more about how apoptosis 

fails in cancer, they also are gaining a greater understanding of 

why many tumors are resistant to 

the killing effects of radiation 

and chemotherapy, which both 

act by inducing cell suicide. 

These insights can inform efforts 

to overcome treatment resistance 

and offer important clues about 

targeted new drugs that encourage selective apoptosis. 

Researchers are exploring how 

apoptosis is regulated, how it 

might be repaired through 

genetic therapies, and how it can 

be selectively triggered, through 

tailored treatments, to induce 

suicide in cancer cells while 

leaving healthy cells alone. 

Triggering Apoptosis 

with New Cancer Drugs 

Clinical trials are currently 

underway to test the efficacy of 

new apoptosis-inducing drugs. 

Velcade, a new agent jointly 

developed by NCI and 

Millenium Pharmaceuticals, targets the proteosome, a device 

inside a cell that functions like 

a cellular “garbage disposal,” 

removing abnormal, aged, or 

damaged proteins. By blocking 

proteosome activity, Velcade 

causes proteins to build up in 

the cell. One of these proteins 

is BAX. In the normal cell, the 

BAX protein promotes apoptosis by blocking bcl-2 activity. 

As BAX levels increase in 

response to Velcade, the cell 

undergoes apoptosis. Velcade 

may prove to be a versatile cancer treatment because it appears 

to be equally effective against 

cancers that do or do not overexpress the bcl-2 gene and 

seems to overcome a tumor’s 

ability to develop chemoresistance. In a Phase II clinical trial 

of patients with progressing 

multiple myeloma, Velcade stabilized the disease in 77 percent 

of the trial participants. Based 

on this encouraging result, 

researchers are planning a Phase 

III trial to compare Velcade to 

dexamethasone, a chemotherapy now used to treat multiple 

myeloma. Other Phase II trials 

will determine the drug’s effectiveness in treating breast cancer, non-small cell lung cancer, 

melanoma, sarcoma, chronic 

myelogenous leukemia, nonHodgkin’s lymphoma, and neuroendocrine and renal cancers. 

Genasense is another apoptosisinducing agent that is being tested for its clinical use. Developed 

by the Genta Company, this 

drug blocks the production of 

the bcl-2 protein and leaves cancer cells more vulnerable to 

apoptosis-inducing chemotherapies. NCI and Genta are cosponsoring clinical trials in lung 

cancer and leukemia patients to 

determine whether pretreatment 

with this drug followed by stateof-the-art chemotherapies 

improves treatment outcome. 

STOR Y OF DISCOVER Y 

A Plan and Budget Proposal for Fiscal Year 2004 71
Extraordinary Opportunity for Investment 

Cancer Communications 

The Opportunity 

From primary prevention to survivorship and end 

of life, only communication can enable people to 

make informed cancer-related decisions and adopt 

behaviors to improve their health. Yet, substantial 

research reveals gaps between the information people want and what they receive. As in other areas of 

life, people with less income and education are also 

disadvantaged with respect to health communication. This is especially evident with patientprovider communication. 

NCI leads our Nation’s cancer communications 

research and development efforts and funds many 

of the Nation’s most innovative and rigorous health 

communications researchers. We are also building a 

substantial storehouse of effective communication 

strategies that are saving lives through interventions 

that reduce smoking, boost fruit and vegetable consumption, and increase the numbers of people who 

are screened for cancer. 

But where we are in communicating about cancer 

is not where we want to be. We must learn more 

about the science of communication and more rapidly translate successful intervention research into 

practice. In particular, we must apply what we have 

learned to improving the health of underserved 

populations. 

Communicating science-based information about 

cancer poses challenges, opportunities, and responsibilities. In this new communications century, our 

ability to use multiple methods of communication 

designed to reach specific audiences and individuals 

is likely to produce greater impact than any single 

approach. 

We understand that for every person who needs 

information about cancer, for every patient and family 

GOAL 

Understand and apply the 

most effective communications approaches to 

maximize access to and 

use of cancer information 

by all who need it. 

member who receives the diagnosis of cancer, the 

experience is individual and unique. Our increasingly 

refined capacity to tailor messages can help translate 

science into useful information for people through 

an ever-expanding menu of communication choices. 

New technologies and tools should extend but not 

replace one-to-one communication between healthcare providers and their patients. 

Our greatest challenge is to work with others to find 

ways to speed the process from discovery to dissemination to assure that caregivers, public health 

officials, patients, and the public have needed 

information at the appropriate time, in a form that 

is comprehensible and useful as well as culturally 

and linguistically appropriate. This is our challenge, 

and it is also our responsibility. 

Progress In Pursuit of Our Goal 

Establishing New Data Collection and 

Analysis Strategies 

The Health Information National Trends 

Survey will be fielded in late 2002 to collect 

nationally representative data every two years from 

8,000 randomly selected adults about the public’s 

need for, access to, and use of cancer-related information. NCI staff are developing protocols to assure 

that the scientific community has rapid access to 

the data and that some reports are created especially for lay persons. In future surveys, we plan to also 

collect data on cancer survivors’ use of different 

media, their risk perceptions, cancer-related behaviors, personal cancer experiences, and perceived 

communications needs. 

Amid the controversy on the efficacy of mammography as a life saving measure this past year, NCI 

quickly mounted an omnibus survey on women’s 

reactions to the mammography controversy. 

Survey results showed that women with lower 

72 The Nation’s Investment in Cancer Research 
levels of education and income were more likely to providing underserved populations with access to


be confused and less likely to have good sources of relevant online cancer information.1 Overall com­


information about mammography. Most participants puter use also increased, including the amount of


indicated that they plan to continue to get mammo- health information sought via the Internet three


grams in spite of the conflicting evidence. months after training. 


Respondents who said they had enough information


to make a decision were more than three times as NCI has launched an improved Web site and


likely to plan on getting screened than women who search engine that combines the information 


said they did not have enough information. These formerly available on NCI’s CancerNet and


findings will inform our future communications cancerTrials sites in user-friendly topical formats.


planning in this area. We are also planning an inter- The first four months following launch saw use


national research effort. increase more than 30 percent.2


Accelerating the Pace of Research and NCI revised Clear Horizons and the Guia para


Development of Interventions dejar de fumar (Guide to Quitting Smoking) as


NCI-funded researchers are assessing the changing part of a smoking cessation project targeted to


information needs of cancer patients under- Medicare beneficiaries in collaboration with the


going chemotherapy and radiation therapy. Centers for Medicare and Medicaid Services.


Study results will help NCI assess the communica- Approximately 10,000 copies of Clear Horizons


tion concerns, problems, patterns, and needs of and 400 copies of the Guia have been distributed.


newly diagnosed patients during active treatment


and the early recovery period. 5 A Day for Better Health is one of the most widely


recognized health promotion messages in the world. 

NCI convened the Consumer-Provider The program is the largest public-private partnership 

Communication Research Symposium in January for nutrition in the United States. The Department 

2002 to bring together eminent scholars from a of Health and Human Services, including NCI and 

broad range of disciplines to identify major gaps the Centers for Disease Control and Prevention, and 

in the research literature on patient-doctor the U.S. Department of Agriculture recently signed 

communications. Gaps identified include the an agreement to formalize and expand their commitneed to better understand the roles played by care- ment to promote the 5 A Day message nationwide, 

givers other than doctors and the nature of their and particularly, in American schools. 

interactions with patients, the changing relationship 

between patient and doctor, the use of diverse set- After a successful pilot, the regional Cancer 

tings and channels, and the need for improved Information Service (CIS) now offers LiveHelp, 

research methodologies. which uses instant messaging technology to provide 

real-time responses to cancer inquiries on NCI’s 

NCI is funding interdisciplinary Centers of Web site, averaging 1,000 user sessions per month. 

Excellence in Cancer Communications CIS plans to pilot LiveHelp again as part of NCI’s 

Research to focus on the advancement of cancer smokefree.gov Web site, scheduled for launch in 

communication science using new and/or improved 2002. In March 2002, one CIS regional office began 

syntheses, theories, methods, and interventions. piloting the use of e-mail to respond to inquiries 

We are also developing and marketing collaborative received through the Web. 

interdisciplinary training and career development 

opportunities for health communication As part of a joint NCI and Agency for Healthcare 

researchers and practitioners. Research and Quality initiative, researchers were 

funded to develop and evaluate a primer to help 

Increasing Access To and people use numbers in health. Three basic risk 

Use of Cancer Information communication tools will supplement the primer: 

Four Digital Divide Pilot Projects were conduct- cancer risk charts, prevention benefit charts, and 

ed in collaboration with NCI’s Cancer Information standard disease summary templates. 

Service (CIS) to identify effective new strategies for 

1 Results at dccps.cancer.gov/eocc/ddpp-awards.html 2 Go to cancer.gov to use this enhanced set of online resources. 

73 ADV ANCING DISCOVER Y AND ITS APPLICA TION 

A Plan and Budget Proposal for Fiscal Year 2004 
The Plan 

Cancer Communications 

GOAL 

Increase knowledge about, tools for, access to, and use of cancer communications by the 

public, patients, survivors, and health professionals — with a special focus on diverse 

populations — to accelerate reductions in the U. S. cancer burden. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Establish new data collection and analysis strategies to support $ 

cancer communications planning and evaluation. 

■ Analyze data from the Health Information National Trends Survey (HINTS), the 

first national communications survey of U.S. populations and make results rapidly 

available to researchers and program planners. 

■ Conduct an Internet-based version of HINTS to determine feasibility of online 

data collection in order to increase response rates and minimize costs. 

■ Conduct a HINTS survey of cancer survivors in parallel with the HINTS public 

survey to collect data on survivors’ use of different media, their risk perceptions, 

cancer-related behaviors, and personal cancer communications experiences. 

■ Conduct regular surveys to assess and analyze the public’s reactions to media 

communications on cancer for use in program planning and evaluation. 

■ Map the information terrain to understand the nature of the information that is 

being provided to different audiences through different media, 

including the Internet. 

■ Assess women’s communication needs related to mammography screening 

worldwide. 

2. Accelerate the pace of research and development of cancer $ 18.50 M 

communication interventions. 

■ Continue to support the Centers of Excellence in Cancer Communications 

Research (Ongoing commitment of $10.00 M per year beginning in Fiscal Year 2003). 

■ Strengthen interdisciplinary research training in strategic areas, including risk 

communications and interactive health communications. 

■ Support basic communications research to accelerate discoveries about how cancer 

information is processed and used. 

■ Support innovative applied communication studies, testing how integrated electronic 

and interpersonal communication systems can improve health. 

■ Create a New Media Collaborative (NewMediaCo) to answer important questions 

about tailored communications and the new media. 

74 The Nation’s Investment in Cancer Research 

4.00 M 

$1.00 M 

$0.50 M 

$0.50 M 

$1.00 M 

$0.50 M 

$0.50 M 

$1.50 M 

$2.50 M 

$5.00 M 

$4.00 M 
ADV ANCING DISCOVER Y AND ITS APPLICA TION 

■ Establish FAST (Facilitate and Accelerate Science and Technology) Track Funding 

for researchers who are conducting health communications research using state-of-the-art 

communications and informatics technologies. 

■ Conduct research to understand and enhance communication between doctors 

and patients. 

3. Develop a communications menu to increase access to and use of $ 

cancer communications by all populations, especially underserved 

populations. 

■ Work with collaborators to fund additional pilot projects to increase Internet access 

and use and evaluate outcomes. 

■ Develop new tools and products to facilitate cancer communications for the public, 

patients and their caregivers, underserved populations, advocacy groups, health 

professionals, and cancer communicators. 

■ Develop a strategic plan and program for low-literacy populations. 

■ Develop and promote a media toolkit to facilitate the media’s use of NCI’s 

resources in preparing cancer-related stories. 

■ Continue to build and nurture the 5 A Day for Better Health program partnerships 

and campaigns to reach underserved populations. 

■ Develop and promote, to grantees and organizations, toolkits for planning 

communications programs, with a special focus on underserved populations. 

■ Develop cancer information for Hispanics/Latinos. 

4. Improve the science of dissemination and the dissemination of $ 

science to assure that all our citizens realize the benefits of 

research investments. 

■ Provide supplemental funding support for investigators to diffuse and disseminate 

NCI-funded evidence-based interventions. 

■ Expand, update, and disseminate the searchable databases of cancer-related 

communication research reports accessible to researchers and program planners. 

■ Conduct research and development on innovative strategies for dissemination. 

Management and Support $ 

Total $39.75 M 

A Plan and Budget Proposal for Fiscal Year 2004 75

$3.00 M 

$2.50 M 

5.75 M 

$1.00 M 

$1.00 M 

$1.00 M 

$0.50 M 

$1.00 M 

$0.50 M 

$0.75 M 

7.50 M 

$4.00 M 

$0.50 M 

$3.00 M 

4.00 M 
New Cancer Communications Efforts Further Accelerate Discovery to Delivery 

Effective communication is critical all along the corridors, from discovery in the laboratory to development of 

new drugs and other interventions to delivery of those interventions in the clinic. With adequate funding in 

Fiscal Year 2004, we can continue and expand current efforts while implementing new initiatives. 

■	 New public surveys to assess reactions to media coverage about cancer will aid us in communication 

planning and evaluation, especially in evaluating the public’s reaction to controversial coverage. 

■	 New training workshops and toolkits about cancer science for journalists will enhance the quality and 

quantity of media coverage about cancer. 

■	 NCI’s International Breast Cancer Screening Network, a voluntary consortium of 25 countries, will develop 

best practices for their international population-based screening mammography programs and standardize and summarize existing information and decision tools for all member countries. 

■	 We will partner with the National Science Foundation or the National Institute of Mental Health to conduct 

basic communications research to accelerate discoveries about how cancer information is processed 

and used. 

■	 Applied communications studies will test how integrated electronic and interpersonal communication systems can improve decision making, facilitate positive changes in health behavior, and improve health. 

■	 A New Media Collaborative will develop theory driven definitions of the active ingredients in tailored communications, agree on common measures, identify a minimum set of essential core mechanisms, and 

conduct process-to-outcome analyses. 

■	 The FAST (Facilitate and Accelerate Science and Technology) Track Funding program will be employed to 

overcome current system barriers that result in long delays in moving ideas to innovative technologies 

and funding. 

NCI has developed an education program entitled 

the Facing Forward Series to equip patients, 

families, and healthcare providers with information 

about what to expect following cancer treatment. 

Publications on cancer survivorship issues for health 

professionals and family care are planned for 2003. 

NCI researchers are studying how to communicate more effectively with low literacy populations. Lessons learned will be synthesized with an 

understanding of the needs of low literacy populations to develop an actionable strategic plan and 

program. NCI currently offers low literacy materials 

on the topics of pain and clinical trials. 

Improving the Science of Dissemination 

and the Dissemination of Science 

NCI has collaborated with the American Cancer 

Society (ACS) to adapt two successful NCI-funded 

intervention studies to create Body & Soul: 

A Celebration of Healthy Living, a nutrition program 

to be delivered through African-American churches. 

The program is an example of effective research dissemination to communities, as well as successful 

research collaboration between NCI and ACS. 

NCI funded the dissemination of two promising 

intervention programs and products: Sunny Days, 

Healthy Ways, Grade 6-8 Sun Safety Curriculum, 

and 5 A Day for Better Health dissemination. 

In the first project, researchers will compare the 

efficacy of disseminating Sunny Days to public 

elementary schools and licensed childcare facilities 

in several areas and test whether dissemination is 

improved by providing Web-based training and 

technical support. 

Launched in January 2002, NewMediacy now has 

more than 300 subscribers. The listserv has summaries of and links to the latest communications 

related data and reports. Important findings include 

data on doctor-patient communications and on the 

public’s use of online health information. 

NCI, in partnership with the Center for the 

Advancement of Health, the Robert Wood Johnson 

Foundation, and the NIH Office of Behavioral and 

Social Sciences Research, is sponsoring a conference on what we know, what we need to know, 

and what we need to do to accelerate the 

adoption of evidence-based cancer prevention 

and control interventions. 

76 The Nation’s Investment in Cancer Research 
Progress against cancer takes place not only in the laboratory 

and the physician’s office but in an environment of heightened 

public health concern. Prevention bolsters our defense against 

cancer. The delivery of quality care is paramount when cancer 

strikes an individual. A network of support is critical to our 

increasing number of survivors, their families, and a population 

that is aging. — Andrew C. von Eschenbach, M.D. 

Addressing Areas of Public 

Health Emphasis 

This past year, as NCI has once again examined its priority research areas, four stand out as 

having special significance not only for increasing our understanding of cancer but for informing aggressive policy decisions and planning for public health programs. We can no longer ignore, for example, the 

pervasiveness of media support for tobacco use in this country. Television and films continue to glamorize smoking and its purported benefits for stress relief, and smoking is still touted to our young far too 

often as a rite of passage to adulthood or as a gateway to approval. 

In our 2004 budget proposal, we give special attention to four areas of public health emphasis. They 

are NCI Challenge areas for Improving the Quality 

of Cancer Care and Reducing Cancer-Related Health 

Disparities and Extraordinary Opportunity areas in 

Cancer Survivorship: Improving Treatment Outcomes 

and Quality of Life and Research on Tobacco and 

Tobacco-Related Cancers. 

We must act on behalf of the millions of people in 

our country today who do not receive appropriate 

care for their cancer, do not get the kind of support 

they need to deal with the emotional, physical, and 

FY 2004 Increase Request for Areas of 

Public Health Emphasis 

(dollars in thousands) 

Quality of Cancer Care $ 27,000 

Reducing Health Disparities $ 

Cancer Survivorship $ 

Tobacco & Tobacco-Related Cancers $ 

Total $210,350 

National Clinical Trials 

Program 49.3% 

Quality of 

Cancer 

Care 13% 

Tobacco & Tobacco-Related 

Cancers 36% 

Reducing Health 

Disparities 29% 

Cancer Survivorship 

22% 

A Plan and Budget Proposal for Fiscal Year 2004 77 

psychological effects of treatment and survivorship, who are affected by cancer. 

ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

61,350 

46,000 

76,000 

or are among the untold numbers who are denied 

proper care because of social position, economic 

status, cultural or language barriers, or geographic 

location. In each instance, we need better science 

to understand the complexities in these areas. 

As we study disparities, we can take action against 

them where the causes are clear. And there is a 

pressing need to address the challenges posed to our 

Nation’s healthcare system by the rising incidence 

of cancer as a result of the aging U.S. population. 

For all Americans, we need evidence-based interventions that will prevent cancer from occurring 

and improve the health and quality of life for those 
NCI Challenge: Building Our Capacity for the Future 

Improving the Quality of Cancer Care 

GOAL 

Improve the quality of cancer 

care by strengthening the 

scientific basis for public and 

private decision making on care 

delivery, coverage, purchasing, 

regulation, and standards setting. 

The Challenge 

The nine million Americans living today who have 

had cancer, including the 1.3 million who will be 

diagnosed in 2002 and the 500,000 who are in the 

last year of life, all hope that they receive the best 

medical treatment and care possible. Unfortunately, 

far too many will not receive this caliber of care. 

The Institute of Medicine’s National Cancer Policy 

Board (NCPB) recently reported that the “ad hoc 

and fragmented cancer care system” in the United 

States “does not ensure access to care, lacks coordination, and is inefficient in its use of resources.” 

Testimonies of cancer patients, families, and 

providers, summarized in the President’s Cancer 

Panel Report, Voices of a Broken System: Real People, 

Real Problems, point to a number of barriers to high 

quality cancer care. These include system and 

financial limitations, the inadequacy of patient 

information and provider education, poor management of cancer-related symptoms, and lack of timely referral to palliative and hospice care.1 

Drawing from the NCPB report, we define quality 

cancer care as the provision of evidence based, 

patient centered services throughout the continuum 

of care in a timely and technically competent manner, with good communication, shared decision 

making, and cultural sensitivity, with the aim of 

improving clinical outcomes, including patient survival and health related quality of life. Substantial 

disagreement exists about what constitutes optimal 

care, especially from the patient’s perspective. 

Therefore, it is critical that we advance understanding of how to measure, monitor, and improve the 

quality of cancer care. We must: 

■ Define core outcome measures and standardize 

core process measures to identify those interventions that have been shown to improve cancer 

care. 

■	 Build a stronger data and methods “infrastructure” for conducting quality of care analyses, 

including studies at both the individual and 

population levels. 

■	 Incorporate symptom management and palliative 

care across the cancer continuum, through cancer 

quality improvement research and translation efforts. 

■	 Ensure that effective therapies demonstrated in 

clinical trials are incorporated into community 

practice. 

■	 Enhance cancer communications for patients, 

their families, and caregivers. 

■	 Strengthen collaborative relationships with 

Federal agencies and private organizations to 

ensure that the best available scientific evidence 

guides cancer care decisions. 

Progress Toward 

Meeting the Challenge 

Developing Core Measurements 

In 2001, NCI convened the Cancer Outcomes 

Measurement Working Group, composed of 35 

internationally recognized experts in measurement, 

oncology, and the social sciences, to assess alternative 

approaches for improving patient centered outcome 

measures such as quality of life, economic burden, and 

satisfaction with care. A major barrier to comparing 

findings is the lack of standardization in measuring 

outcomes, like health related quality of life. In 

response, working group members recommend that 

outcome measures be selected from the small set 

that has been adequately validated. In addition, NCI 

should support research to improve our ability to 

compare study findings, conduct sound metaanalyses, and adopt user friendly, computer adaptive 

survey administration. 

Standards for process measures of quality cancer care 

are being developed through a major new NCI 

78 

1 Institute of Medicine, National Research Council, Ensuring Quality Cancer Care, 1999. 

President’s Cancer Panel, Report of the Chairman 2000-2001, Voices of a Broken System: Real People, Real Problems, September 2001. 

The Nation’s Investment in Cancer Research 
A Plan and Budget Proposal for Fiscal Year 2004 

■ 

■ 

■ 

■ 

collaboration with other Federal agencies and the of Clinical Oncology (ASCO) is conducting a similar 

private sector. This Cancer Care Quality study, focusing on breast and colorectal cancer, as 

Measurement Project (CanQual), conducted part of its National Initiative on Cancer Care Quality. 

under the auspices of the non-profit National NCI and ASCO have signed a Memorandum of 

Quality Forum, is identifying core process measures Understanding that stresses sharing information and 

for treatment, survivorship, and end-of-life care for progress on these complementary efforts. The 

the major tumor sites, as well as measures that forerunner to CanCORS is the landmark Prostate 

apply to all tumor sites, such as palliative care. Cancer Outcomes Study, the first longitudinal 

study of quality of life for men living with prostate 

Strengthening the Science Base cancer. (See sidebar on this page.) 

NCI established the Cancer Care Outcomes 

Research and Surveillance Consortium NCI’s recently established Patterns of 

(CanCORS) in 2001, launching a single study of Care/Quality of Care Program (POC/QOC) is 

treatment patterns and quality of care over time in drawing from the Surveillance, Epidemiology, and 

large cohorts of newly identified cancer patients. End Results (SEER) registry data to investigate 

CanCORS investigators are combining data from adoption of recommended treatments for the most 

registries, medical records, insurance claims, and common cancers. POC/QOC studies provide the 

patient and provider surveys to assess the care most authoritative data on trends in treatment patreceived by a sample of 5,000 colorectal and 5,000 terns for breast, colorectal, and ovarian cancer and 

lung cancer patients across the United States. This results will be disseminated through professional 

research will investigate the impact of selected education activities in collaboration with professioninterventions on patient centered outcomes, dis- al societies. The Cancer Research Network, a 

semination of state-of-the-art therapies in the com- consortium of researchers affiliated with 10 major 

munity, modifiable risk factors, and disparities in not-for-profit HMOs, has provided the mechanism 

cancer care and outcomes by racial/ethnic group and for NCI to obtain better data more quickly on patsocioeconomic status. Recognizing the potential terns of cancer care from multiple perspectives. 

value of large cohort studies, the American Society The work of the Breast Cancer Surveillance 

79 ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

A Plan and Budget Proposal for Fiscal Year 2004 

reatment Choices 

The Prostate Cancer Outcomes Study (PCOS), the most comprehensive survey ever undertaken on 

prostate cancer outcomes, was initiated in 1994 to evaluate variations in practice and the impact of 

therapies on health related quality of life. Study findings are helping men, their families, and clinicians 

make more informed choices about treatment alternatives. They include: 

Reports showing that, while physicians order bone scans on approximately two-thirds of all new 

prostate cancer patients and computed tomography (CT) exams on about one-third of new patients, 

less than five percent of the imaging studies done for newly diagnosed prostate cancer patients show 

evidence of metastases. In contrast, for men with serum PSA levels greater than 50 ng/ml and Gleason 

scores ranging from 8-10, the imaging studies were positive in over 60 percent of the cases. 

Evidence that men with clinically localized prostate cancer who are treated with a radical prostatectomy 

are more likely to experience urinary and sexual dysfunction than those treated with external beam 

radiation therapy. Bowel dysfunction, on the other hand, is more common among men receiving 

external radiation therapy. 

Evidence that men aged 75 or older more often received conservative treatment, such as hormonal 

therapy alone or watchful waiting, than aggressive treatment such as radical prostatectomy or 

radiation therapy. 

A finding that for men younger than 60, use of aggressive treatment was similar among white, 

African-American, and Hispanic men. Among men 60 years old and older, African American men 

underwent aggressive treatment less often than did white men or Hispanic men. 

NCI plans to follow the 3,500 PCOS participants for 10 years after diagnosis to ascertain and verify deaths, 

maintain contact with respondents, and conduct a survey ten years out to assess long-term changes in 

disease-related quality of life.2 

2

appliedresearch.cancer.gov/PCOS/index 

Prostate Cancer Outcomes Study Sheds Light on T
The Plan 

Improving the Quality of Cancer Care 

GOAL 

Improve the quality of cancer care by strengthening the scientific basis for public and private 

decision making on care delivery, coverage, purchasing, regulation, and standards setting. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Develop core process and outcome measures for assessing the $ 5.50 M 

quality of cancer care. 

■ Support research to improve patient-centered outcomes measurement, including 

development of tools to enhance data collection and statistical studies to facilitate the 

“cross-walking” of scores among competing instruments. 

■ Continue to provide supplemental funding for the Cancer Care Quality Measurement 

Project to identify additional core process measures. 

■ Support research to evaluate and enhance dissemination and use of core process 

measures and develop new measures where needed. 

2. Strengthen the methodological and empirical foundations of $15.00 M 

quality of cancer care assessment. 

■ Sustain support at $7.5 million per year for Cancer Care Outcomes Research and 

Surveillance Consortium studies. 

■ Sustain support for Cancer Research Network population laboratories at $5.0 million 

per year for cancer control research, with additional emphasis on the quality of cancer 

care in community settings. 

■ Support Pattern of Care/Quality of Care (POC/QOC) studies on levels, trends, 

variations, and dissemination of effective treatments and collaborate with other 

Federal agencies and professional societies for education on quality of care 

improvement. Provide support for new Rapid Response Special Studies (RRSS) 

to facilitate methodological and pilot investigations. Integrate results from 

these studies with Cancer Intervention Surveillance Modeling Network 

models to predict the effects of treatment dissemination on trends in survival 

and mortality. 

■ Increase support for analyses of the Surveillance, Epidemiology, and End Results 

and Medicare (SEER-Medicare) database to investigate the use and outcomes of 

selected cancer interventions. 

■ Based on results of completed and ongoing POC/QOC, SEER-Medicare, and RRSS 

studies, support intervention studies and demonstration programs for improving referral 

patterns and treatment where sub-optimal performance has been documented. 

■ Based on ongoing feasibility studies, link tumor registry information to Medicaid and 

private payer administrative data to investigate whether interventions are reaching and 

improving the health of individuals aged 65 or younger. Assist private insurers in creating 

and analyzing claims linked to tumor registry data by leading a workshop based on the 

experience of SEER-Medicare and SEER-Medicaid investigators. 

■ Continue to support innovative research on economic and delivery system determinants 

of the quality of and return on investment for new clinical approaches to prevention, 

screening, and treatment services. 

80 The Nation’s Investment in Cancer Research 

$2.00 M 

$1.00 M 

$2.50 M 

$3.00 M 

$2.00 M 

$2.00 M 

$2.00 M 

$2.50 M 
ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

■ Sponsor new studies to strengthen the methodological foundations of outcomes 

research and quality of care assessment, including studies on the integration of 

evidence based performance measures at provider and health system levels. 

■ Support the establishment of physician networks and databases for tracking and 

monitoring cancer screening practices. 

3. Incorporate symptom management and palliative care into the $ 

full spectrum of cancer quality improvement research and translation 

efforts, from initial treatment, through survivorship, and 

at the end of life. 

■ Integrate existing and newly developed knowledge about effective symptom 

management and palliative care. 

■ Incorporate evidence based palliative care practices more fully into NCI’s 

education and information products and spotlight Internet accessible information. 

■ Educate health professionals on ways to better integrate and deliver symptom 

management and palliative care, using best-practice standards. 

4. Enhance quality of care research within, and beyond, the $ 

NCI clinical trials program. 

■ Sponsor meetings to bring together leading researchers and stakeholders to 

assess the state of the art, identify key research questions, and develop a strategy 

for assessment of patient outcomes for clinical trials. Disseminate resulting 

information. 

■ Using knowledge gleaned from a workshop on the diffusion of medical innovations, 

support studies examining the rates and patterns of adoption of important therapies 

across the entire spectrum of delivery systems. 

5. Improve the quality of cancer care by strengthening cancer 

communications. (See Cancer Communications plan, pages 72-76.) 

6. Ensure that the best available scientific evidence about quality $ 3.00 M 

measures and assessment informs Federal decision making. 

Share new knowledge and collaborate to identify, develop, 

and monitor progress on core measures of cancer care quality. 

■ Continue to support interagency demonstration projects organized through the Quality 

of Cancer Care Committee (QCCC), a forum for coordinating Federal activities. $2.00 M 

■ Capitalize on the collective clinical and policy expertise of the QCCC to provide 

technical assistance and advice to public agencies and private organizations upon request. 

■ Foster collaboration among QCCC members (particularly the Centers for Disease 

Control and Prevention, the Centers for Medicare and Medicare Services, and the 

Agency for Healthcare Research and Quality), the states, and private organizations 

to support ongoing development of a national cancer data system for monitoring 

trends in cancer care and identifying population disparities. 

Management and Support $ 1.00 M 

Total $27.00 M 

A Plan and Budget Proposal for Fiscal Year 2004 81

$2.00 M 

$1.50 M 

1.00 M 

1.50 M 

$0.50 M 

$1.00 M 

$1.00 M 
NCI Collaborates with Federal Partners To Ensure That the Best Available 

Evidence Informs Decision Making 

Through the Quality of Cancer Care Committee, NCI currently supports three interagency projects: 

■	 The Health Resources and Services Administration and Centers for Disease Control and Prevention 

collaborative to build on a chronic care model to develop “breakthrough changes” to improve screening, 

referral, and follow-up for breast, cervical, and colorectal cancer for underserved populations. 

■ The Centers for Medicare and Medicaid Services collaborative to increase awareness and improve delivery 

of the Medicare colorectal cancer screening benefit among Medicare beneficiaries and their physicians. 

■ The Department of Veterans Affairs (VA) collaborative to improve use of evidence about good practice for 

ongoing improvements in screening, surveillance, treatment, and end-of-life care for colorectal cancer in 

the VA healthcare system.3 

3 hsrd.research.va.gov/queri/CRC_web_announcement.doc 

Consortium investigates factors associated with 

high quality screening mammography in community practice, including hormone replacement therapy 

and breast density, family history, age, and examination technique. 

Studies linking SEER and Medicare data 

continue to provide insight into quality of care issues


including: 


■ Nearly equivalent costs of breast conserving 


surgery versus mastectomy for early-stage breast 

cancer. 

■	 Potential disparities by race, ethnicity, or age 

in the receipt of chemotherapy for colon and 

ovarian cancer. 

■	 Significantly reduced rates of postoperative and 

late urinary complications for men undergoing 

prostatectomy, when performed in a highvolume hospital by a surgeon who performs a 

high number of such procedures. 

Improving Symptom Management and


Palliative Care across the Cancer


Continuum


The Improving Palliative Care for Cancer report 4


from the Institute of Medicine’s National Cancer


Policy Board identified gaps in symptom manage­


ment and palliative care research. Information on


how to better measure, evaluate, and improve


symptom management is now emerging from a 


variety of initiatives: 


■ Research supported by NCI through the Cancer


Outcomes Measurement Working Group, 

CanQual, CanCORS, and Quality of Cancer 

Care Committee projects 

■	 The 2002 NIH State-of-the-Science Conference 

on Symptom Management in Cancer: Pain, 

Depression, and Fatigue 

■ Clinical trials on supportive and palliative care 

topics such as cachexia, pain, and symptom 

reduction as well as new research concepts that 

examine depression in cancer patients through 

the NCI Community Clinical Oncology Program 

■ NCI- and NIH-supported studies on complementary and alternative medicine at the end of life 

Enhancing Quality of Care Research within the NCI Clinical Trials Program 

The NCI National Clinical Trials Program 

provides an ideal venue to assess quality of care 

through the incorporation of valid and reliable 

health related quality of life endpoints into 

clinical study design. A workshop on the diffusion 

of medical innovations will be held in 2003, setting the stage for studies to examine why some 

highly promising therapies successfully move into 

clinical practice while others do not. 

Strengthening Cancer Communications 

Ultimately, improved cancer care depends on our 

ability to communicate messages about prevention, treatment, patient care, survivorship, and 

end-of-life issues to the research community, care 

providers, patients, and payers. See pages 72-76 

for information on NCI cancer communication 

efforts. 

Ensuring That the Best Available Science 

Informs Decision Making 

NCI established the Quality of Cancer Care 

Committee (QCCC) in 2000 to improve the quality of Federal-level decision making about cancer 

care. Its membership includes the Federal agencies involved in cancer care delivery, coverage, 

regulation, standards setting, or conducting 

research on the quality of cancer care. (See 

sidebar at the top of this page.) 

82 

4 Institute of Medicine, National Research Council, Improving Palliative Care for Cancer, 2001. 

The Nation’s Investment in Cancer Research 
Sustained Investment in Studying Cancer Trends 

Improves Knowledge and Understanding of Cancer 

This is a report on progress toward objectives outlined in previous years as part of the NCI 

Challenge for Studying Emerging Trends in Cancer. While we are not requesting additional funding 

increases in this area, the following efforts will continue to produce the information and resources 

needed for high quality, well informed research, program planning, and health policy. 

Progress Report for NCI Challenge: 

Studying Emerging Trends in Cancer 

The Surveillance, Epidemiology, and End 

Results (SEER) Program serves as the foundation 

for a national system of data resources on all aspects 

of cancer surveillance. We have: 

■ Increased coverage and made it more representative of the entire population, including 

racial/ethnic minorities and groups living in rural 

areas — through expansion and partnerships 

with the Centers for Disease Control and 

Prevention and state cancer registries. 

■ Expanded quality data on risk factors; health 

behaviors; extent of disease, treatment, and 

lifestyle; and quality of life for cancer survivors 

— through public and private partnerships. 

■ Provided scientists with information (generated 

by Economic Studies in Cancer Prevention, 

Screening, and Care and Cancer Surveillance 

Using Health Claims-Based Data Systems) to 

assess trends, quality, and the cost of cancer care. 

■ Conducted Patterns of Care studies to assess the 

quality of care that cancer patients receive.1 

We have new research methods in place to monitor cancer interventions, ensure the accuracy of 

questionnaires for self reporting, track nutritional 

health objectives, and estimate the economic cost 

of cancer. For example: 

■ The Cancer Intervention and Surveillance 

Modeling Network uses computer-based modeling to study the need for and the effectiveness 

of cancer interventions. 

■ The recently completed study, Observing 

Protein and Energy Nutrition, is improving 

our ability to use and interpret dietary 

assessment data.2 

■ The Family History of Cancer Assessment 

Study is assessing the accuracy of reports of 

cancer family histories. 

NCI is also co-funding, with the National Science 

Foundation, projects in data visualization, software 

Our data system and methodological resources 

are being distributed widely and integrated into 

a number of public and private sector efforts. 

For example: 

■ The Atlas of Cancer Mortality shows geographic 

patterns of cancer death rates and a companion 

Geographic Information Systems provides tools 

for using the Atlas. 

■ The Cancer Profiles system identifies areas in 

greatest need of cancer control activities. 

■ The Tobacco Use Supplement to the Current 

Population Survey tracks progress in tobacco 

control. 

■ The Diet History Questionnaire is used for 

epidemiologic and surveillance studies. 

■ The National Health Interview Survey Cancer 

Control Topical Module is used to evaluate 

national progress in achieving cancer objectives. 

The annual Cancer Progress Report, first released in 

2001, informs the public, policy makers, advocates, 

and health professionals of progress in the Nation’s 

fight against cancer. 

3 The Annual Report to the 

tion with several partners, provides an update on 

cancer rates and trends in the United States.4 

For more detail about these and other similar 

initiatives, go to appliedresearch.cancer.gov 

and surveillance.cancer.gov. 

1 See page 79 for more information. 

2 See page 52 for more information. 

3 progressreport.cancer.gov 4 seer.cancer.gov/reportcard 

for geospatial analysis, and graphical display of data. 

Nation on the Status of Cancer, published in collaboraPROGRESS REPOR 

83 T 

A Plan and Budget Proposal for Fiscal Year 2004

NCI Challenge: Building Our Capacity for the Future GOAL 

Understand the fundamental 

causes of health disparities 

in cancer, develop effective 

interventions to reduce these 

disparities, and facilitate their 

implementation. 

Reducing Cancer-Related Health Disparities 

The Challenge 

The unequal burden of cancer in our society is 

more than a scientific and medical challenge. It is 

a moral and ethical dilemma for our Nation. Certain 

populations experience significant disparities in 

cancer incidence, the care they receive, and the 

outcomes of their disease. These differences have 

been recognized, or at least suspected, for some 

time. Now, they are being documented with 

increasing frequency and clarity. 

Our challenge today is to: 

■	 Fully understand the fundamental causes of cancer health disparities, including the influence of 

social position, economic status, cultural beliefs 

and practices, environmental exposures, genetics, and individual behavior. 

■ Develop effective interventions to address these 

disparities. 

■ Actively facilitate their implementation. 

If there are ways we fund or perform cancer research 

that favor one person or group over another, we must 

discover and mend those ways. If there are ways we 

distribute the benefits of our research that contribute to the very real social and economic disparities in who develops cancer, who survives cancer, 

and the quality of that survival, we must improve 

our distribution. And if we can influence policy to 

improve care, we must exercise that influence. 

Recognizing that disparities must be overcome if 

we are to significantly reduce the Nation’s cancer 

burden, NCI established a dedicated center to 

direct and coordinate an Institute-wide plan to 

address key disparity issues. The scope of planning 

will incorporate all research areas within NCI’s organizational structure — basic biology, epidemiology, 

genetics, prevention, communication, cancer control, diagnostics and treatment development, and 

survivorship. 

Healthcare policymakers, providers, payers, and 

other stakeholders must be empowered to provide 

equal access to proven interventions for cancer prevention and control for all populations. NCI must 

collect and synthesize the scientific evidence and 

provide leadership to help ensure that policies and 

services bring the benefits of research to all Americans. 

Progress Toward 

Meeting the Challenge 

NCI is working to identify cancer health disparities 

and their underlying causes. For example, NCI, 

together with national, state, and local partners, is 

investigating the causes of disparities in cervical 

cancer mortality. While mortality for this disease 

has fallen three-fold nationwide in the past 50 years, 

some geographic areas experience persistently high 

cervical mortality rates. Researchers, clinicians, 

patient advocates and others will meet to review 

surveillance and background data for high mortality 

areas and articulate the key issues and recommendations for action. This information will be disseminated to Federal, state, and local policy makers. 

NCI has funded a landmark, five-year Southern 

Community Cohort Study that will enroll and 

follow 105,000 people — two thirds of whom will 

be African Americans — in six southeastern states 

to determine why African Americans are more likely to develop and die from cancer. Genetic, environmental, and lifestyle factors that contribute to cancer development will be identified, and important 

health information about low income and rural populations of all races is also anticipated. 

NCI has launched an investigation into the impact of 

the “racialization” of scientific inquiry and disparate 

patient outcomes. We are also working to establish 

interdisciplinary research Centers for Population 

Health and Health Disparities to better understand the interaction of social, cultural, and physical 

84 The Nation’s Investment in Cancer Research 
environmental determinants of cancer incidence and 

outcomes and the behavioral and biologic factors that 

contribute to them. This trans-NIH initiative is also 

supported by the National Institute of Environmental 

Sciences, the National Institute on Aging, and the 

Office of Behavioral and Social Science Research and 

seeks to develop more effective interventions. 

The California Health Interview Survey, sampling 

more than 55,000 respondents, is expanding understanding of the interplay of race, ethnicity, socioeconomic factors, and other social and cultural influences on 

cancer risk factors such as tobacco use, diet, and screening. With several partners, NCI has implemented programs to address the cancer health disparities that are 

being identified. For example, NCI sponsors 18 Special 

Populations Networks for Cancer Awareness 

Research and Training that build relationships with 

community-based programs, foster cancer awareness 

activities, increase minority enrollment in clinical trials, pilot projects that will lead to the development 

of grant applications for new and innovative research, 

and develop junior biomedical researchers from 

minority and underserved communities. 

Collaborations with NCI Divisions and clinical/academic partnerships among Network awardees and 

Cancer Centers, academic institutions, and Clinical 

Cooperative Groups are essential to all of these 

activities. 

NCI is partnering with the Health Resources and 

Services Administration, the Centers for Disease 

Control and Prevention, and the Institute for 

Healthcare Improvement in a Health Disparities 

Collaborative to improve delivery for underserved 

populations throughout the United States. The 

Collaborative focuses on colorectal, breast, and cervical cancer screening and clinical follow-up for people 

who traditionally lack access to quality healthcare. 

In 2003, the radiation oncology-based Cancer 

Disparities Research Partnerships Program 

will expand radiation oncology clinical trials in three 

geographically dispersed institutions serving large 

numbers of Native Americans, African Americans, 

Hispanics and rural Appalachians. The program is 

also expanding dissemination and diffusion channels using novel telemedicine and teleconferencing 

to connect participating institutions, their academic 

partners, and NCI clinical facilities and experts. 

NCI continues to provide health disparities training for new scientists through the Cancer 

Prevention Fellowship Program. Interest in health 

disparities continues to grow, with 6 of 15 entering 

fellows in 2002 expressing strong interest compared 

with none in 1999. In 2003, the Cancer Disparities 

Research Partnerships Program will support minority 

clinical investigators, nurses, data managers, and 

others at institutions new to cancer disparities 

research. 

Researchers examined racial and 

A Plan and Budget Proposal for Fiscal Year 2004 

ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

85 

-Related Health Disparities 1 

Social Circumstances May Contribute to Lower Survival Among African Americans with Advanced NonSmall Cell Lung Cancer (NSCLC). Researchers assessed more than 500 patients receiving systemic chemotherapy 

for advanced NSCLC, between 1989-1998, and found that African Americans in the study were more likely to present 

with a poor performance status and greater weight loss. African Americans in the study were also more likely to be 

unmarried, disabled, unemployed, or Medicaid recipients, suggesting that social circumstances may be the cause of 

poorer prognostic profiles in African Americans. 

Educational Interventions Increase Cervical Cancer Screening Among Chinese Americans. NCI-supported 

investigators in Seattle found that direct mailing of culturally and linguistically appropriate educational materials and 

home visits by outreach workers can increase participation in cervical cancer screening in the Chinese-American 

population. 

1 

cancer risk for these populations. 

and socioeconomic factors is needed to better explain disparities and determine how this information can help r

African American Men Are at Greater Risk for Advanced Prostate Cancer. 

ethnic differences among men who develop advanced prostate cancer and found that African American men were 

at greater risk of advanced disease than Hispanic men and had about twice the risk of non-Hispanic Whites. After 

adjusting for clinical and sociodemographic variables, such as higher socioeconomic status, the difference for African 

Americans persisted but disappeared for Hispanics. Additional research on biologic markers, genetic susceptibility, 

See also Highlights of Progress, pages 8-13. 

educe 

Results of Recent Research on Cancer
The Plan 

Reducing Cancer-Related Health Disparities 

GOAL 

Understand the fundamental causes of health disparities in cancer, develop effective 

interventions to reduce these disparities, and facilitate their implementation. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Expand research on the causes of health disparities in cancer. $16.20 M 

■ Identify gaps in research for cancer health disparities by reviewing Federal and voluntary organization research portfolios. Use findings to update NCI’s strategic plan, 

guide research and partnership efforts, and set priorities for new cancer health 

disparities research support. 

■ Expand the knowledge base through fundamental cancer control research, including: 

– International collaborative studies on social determinants of cancer and cancerrelated disparities through supplements to NCI-supported Centers for Population 

Health and Health Disparities. 

– Expanded epidemiologic studies exploring racial/ethnic cancer disparities. $3.00 M 

– Investigations of physician, patient, and health system factors influencing cancer 

care quality among racial/ethnic minorities and other underserved populations. 

$3.00 M 

– Research on biologic pathways through which behavioral, social, physical, and 

environmental factors influence cancer-related health disparities, including genetic 

polymorphisms, psychoneuroimmunologic factors, and differential responses to 

therapy. 

2. Develop effective interventions to reduce cancer health disparities. $ 9.50 M 

■ Increase collaborative research among the Special Populations Networks for Cancer 

Awareness Research and Training, NCI, and other Federally funded research networks. 

■ Assess the efficacy and cost effectiveness of patient navigator programs in populations 

experiencing serious cancer-related health disparities. 

■ Collaborate with service delivery components of the Federal government to support 

new intervention research for women who have not been screened or who are substantially under screened for breast and cervical cancer, emphasizing sociocultural 

determinants in planning, implementing, and evaluating these interventions. 

■ Address disparities in risk, access to prevention interventions, quality cancer care, and 

clinical trials through formal affiliations and supplemental funding to NCI Cancer 

Centers using existing links with and direct funding to Minority-Serving Institutions. 

$2.00 M 

3. Expand our ability to define and monitor cancer-related health disparities. $ 6.00 M 

■ Enrich understanding of cancer health disparities through new population-based state 

and regional surveys that provide information on socioeconomic and cultural factors. 

$1.00 M 

■ Conduct methodologic research to ensure cross-cultural equivalence in survey, 

epidemiological, and clinical research involving cancer risk factors. 

■ Collect risk factor and screening data for small populations defined by geographic, 

racial/ethnic, socioeconomic, and other characteristics. 

86 The Nation’s Investment in Cancer Research 

$5.20 M 

$2.00 M 

$3.00 M 

$3.00 M 

$1.00 M 

$3.50 M 

$1.00 M 

$4.00 M 
ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

4. Facilitate the implementation of new policy, community and clinical $ 17.90 M 

interventions, and evaluate their impact on health disparities. 

■ Support a series of meetings with representative stakeholders to review evidence, 

develop collaborations, and create action plans for interventions to reduce or 

eliminate cancer health disparities. 

■ Increase minority and underserved population access to state-of-the-art prevention 

and treatment clinical trials: 

– Expand clinical trials outreach to under-represented populations and increase 

participation in trials at established minority-based oncology sites. 

– Provide supplements to fund a nurse case manager and a patient navigator at each 

of approximately 15 Cancer Centers, 20 Cooperative Group sites, and 10 

Community Clinical Oncology Program sites that have demonstrated a 

commitment to expand minority participation in clinical trials. 

■ Expand dissemination and promotion of research results and evidence based 

interventions to reduce cancer health disparities. 

– Expand local and regional partnerships to overcome health disparities among 

medically underserved populations. 

communities with similar infrastructure barriers. 

– Expand support for research-practice partnerships between Federally funded 

cancer control investigators and state and local health program practitioners to 

increase community based cancer prevention and control research and evidence 

based interventions in underserved communities. 

– Establish a Dissemination/Diffusion Research Grants Program to (1) study social, 

environmental, and behavioral barriers to adopting evidence-based cancer 

prevention and control interventions by public health officials and community 

clinicians, (2) test new hypotheses for reaching underserved populations in underresourced community health settings, and (3) develop, apply, and evaluate 

dissemination and diffusion interventions to reduce cancer health disparities. 

– Expand NCI’s integrated low literacy program by customizing cancer information 

materials for targeted audiences. 

5. Expand minority investigator competition for and minority $ 

population involvement in health disparities research. 

■ Recruit 3 additional minority scientists and physicians to the Cancer Prevention 

Fellowship Program to focus on health disparities research. 

■ Expand the Continuing Umbrella of Research Experiences Program to encourage 

high school to graduate level minority students to enter careers in health disparities 

research. 

■ Increase minority participation in clinical trials through an NCI fellowship training 

program for healthcare providers and other forums. 

■ Expand support for the Science Enrichment Program to attract minority high school 

students to careers in science and medicine. 

■ Fund 20 new cancer education grants for healthcare provider continuing education, 

outreach programs in underserved communities, and accrual of minority and underserved populations to NCI-supported treatment and prevention trials. 

Management and Support $ 

Total $61.35 M 

A Plan and Budget Proposal for Fiscal Year 2004 87

$0.50 M 

$3.00 M 

$4.40 M 

Disseminate models for success to 

$2.50 M 

$2.00 M 

$4.00 M 

$1.50 M 

9.75 M 

$0.75 M 

$2.00 M 

$1.00 M 

$1.00 M 

$5.00 M 

2.00 M 
Extraordinary Opportunity for Investment 

Cancer Survivorship: 

GOAL 

Reduce the adverse 

effects of cancer diagnosis and treatment and 

optimize outcomes for 

cancer survivors and 

their families. 

Improving Treatment Outcomes and Quality of Life 

The Opportunity 

Entering the new millennium armed with new 

insights into biology, including information from 

the sequencing of the human genome, we are 

beginning to see the fruits of the “War on Cancer” 

launched in 1971. Once almost uniformly fatal, 

cancer has become for many, a chronic illness, and 

for growing numbers, a curable disease. There are 

an estimated 8.9 million cancer survivors in the 

United States today. An impressive 14 percent of 

these individuals were originally diagnosed over 

20 years ago. 

Cancer survival has risen steadily over the past 

three decades for all cancers combined. In the 

absence of other competing causes of death, current 

figures indicate that for adults diagnosed today, 

60 percent can expect to be alive five years later. 

As past and future advances in cancer detection, 

treatment, and care diffuse into clinical practice, 

the number of survivors can be expected to increase. 

Fewer deaths from cardiovascular disease and the 

aging of the population will contribute to this trend. 

While cancer survivors are living longer, we have 

limited knowledge and many questions about the 

health status, functioning, and quality of life for most 

of those who are post-treatment: What are the most 

common late effects of treatment? Who is 

at risk and can they be protected? Can treatmentrelated injury to normal tissue be prevented or 

reversed? What proportion of survivors will experience recurrent or second malignancies? Who should 

be following these survivors to detect disease recurrence? What constitutes “optimal surveillance” and 

what is the cost of such follow-up care? Do medical, 

psychosocial, or behavioral interventions reduce morbidity in these populations? 

What is clear is that most of our current treatments, 

although benefiting the patient overall, will produce 

some measure of adversity. In some cases, these 

effects can have a profound impact on survivors’ 

health and quality of life. For example: 

■ A quarter of deaths among childhood cancer survivors are due to late consequences of treatment 

— e.g., second malignancies, cardiac failure. In 

one large study, 46 percent did not believe that 

their treatment could have put them at later risk 

for a serious health problem. This knowledge 

gap has implications for optimal care. 

■	 Breast and lymphoma patients exposed to 

systemic chemotherapy are at increased risk for 

problems with cognitive functioning and some 

may be genetically more susceptible to this 

chronic effect of treatment. 

■	 Between a quarter and a third of patients undergoing bone marrow or stem cell transplant suffer 

from symptoms of post-traumatic stress disorder 

(PTSD). Similar numbers of parents (especially 

mothers) of children treated for cancer also experience PTSD symptoms, even years after their 

children are treated. 

■	 Female brain cancer survivors are eight times 

more likely to experience separation or divorce 

than male survivors. 

The adverse effects of cancer treatment remain 

poorly documented and understood. As presently 

configured, our surveillance databases (e.g., from 

NCI’s Surveillance, Epidemiology, and End Results 

Program and other tumor registries) often cannot 

identify a patient’s current health status and phase of 

survivorship — whether in active treatment, disease 

free, or dying of cancer. More research is needed to 

address issues of survivorship for specific cancers as 

well as for populations that have been under-represented in previous research, such as the elderly. 

Cancer survivors and their family members face 

unique and uncharted consequences of illness and 

treatment. Information about survivors is critical if 

we are to: 

88 The Nation’s Investment in Cancer Research 
■ Help patients make decisions now about treat- their families experience significant psychosocial 

ment options that will affect their future. outcomes: fear of recurrence, sense of isolation, 

■ Tailor therapies to maximize cure while minimiz- anxiety and depression, employment and insurance 

ing adverse treatment related effects. discrimination, altered body image, and relationship 

■	 Develop and disseminate evidence based inter- difficulties. While we know that human behavior 

ventions that reduce cancer morbidity as well as can have a profound impact on how cancer is 

mortality and facilitate adaptation among cancer managed and may also affect disease-free or overall 

survivors. survival, we are not currently using this information 

■	 Improve quality of care, control costs, and equip in the systematic delivery of care. Nor do we underthe next generation of physicians, nurses, and stand cancer’s consequences for millions of family 

other healthcare professionals to provide not just members affected by this illness, many of whom 

the science but also the art of comprehensive may themselves be at increased risk for cancer due 

cancer medicine. to shared cancer causing genes, lifestyle, and/or 

toxic exposures. As cancer care increasingly is 

Recent Institute of Medicine reports have identi- pushed into the outpatient setting, the economic, 

fied the need for the following survivorship research physical, and emotional burden on family members 

that will lead to increased length and quality of life is increasing. We have, to date, failed to fully apprefor those diagnosed with cancer.

1 ciate this additional at-risk population or taken 

advantage of the opportunity to provide these vital 

Monitoring Adverse Long-Term or Late caregivers with supportive or health-promoting 

Effects of Cancer and Its Treatment interventions as part of standard cancer care. 

As children and adults with a history of cancer are 

living longer and data from NCI research studies are Understanding Genetic 

maturing, the nature and extent of long-term and Risk and Treatment 

late effects are being documented and reported: It is expected that with the decoding of the human 

neurocognitive problems, premature menopause, genome, our ability to identify hereditary cancer 

gastrointestinal system dysfunction, cardiorespirato- risk patterns and genes associated with susceptibiliry system dysfunction, sexual impairment, infertility, ty to treatment-related late effects will accelerate. 

chronic fatigue and pain syndromes, second malig- Using tissue and blood samples from survivors to 

nancies, and others. Identification of patients at track outcomes holds the promise of helping us 

increased risk for complications of treatment and to better understand how cancer-causing genes 

information on interventions to reduce those risks operate and what therapies may be effective in 

will help patients, their families, and their providers controlling their effects. It will also permit us to 

negotiate critical decisions. With NCI’s recent expan- understand which therapies work best and for 

sion of the Surveillance, Epidemiology and End whom they are successful. An increasing number 

Results and National Clinical Trials Programs, our of cohort studies2 are focusing on cancer survivors. 

ability to track and monitor disease and care-related 

outcomes among survivors through these types of Training Researchers and 

surveillance mechanisms is developing. Disseminating Research Findings 

It is critical to disseminate the resulting research 

Understanding the Role of Behavioral findings across disciplines so that clinicians and 

and Socio-Cultural Factors in Patient researchers and other experts from the biomedical 

Outcomes and social sciences can use the new knowledge for 

There is growing appreciation of the role that socio- further research, intervention development, trend 

cultural and behavioral factors play in patient out- analysis, and advocacy. 

comes. Research shows that many survivors and 

1 Ensuring Quality Cancer Care, 1999. nationalacademies.org/publications 

Improving Palliative Care for Cancer, 2001. nap.edu. 

Improving Palliative Care for Cancer, Summary and Recommendations, 2001. nap.edu. 2 In a cohort study, the same patient group is studied over a period of time. 

ADDRESSING AREAS OF PUBLIC HEAL 

89 TH EMPHASIS 

A Plan and Budget Proposal for Fiscal Year 2004 
90 The Nation’s Investment in Cancer Research 

The Plan 

Cancer Survivorship: reatment Outcomes and Quality of Life 

GOAL 

Reduce the adverse effects of cancer diagnosis and treatment and optimize outcomes for 

cancer survivors and their families. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Expand research efforts to understand the biological, physical, $9.50 M 

psychological, and social mechanisms, and their interactions, 

that affect a cancer patient’s response to disease, treatment, 

and recovery. 

■ Fund cohort and case control studies that examine the prevalence and incidence of 

late effects, in particular among survivors five or more years post-diagnosis. 

■ Fund behavioral and epidemiological studies that examine both negative and positive 

physiologic and psychosocial effects, and their correlates, of cancer on survivors who 

are post-treatment. 

■ Identify the genetic and/or phenotypic markers of susceptibility to treatment-related 

adverse effects and gene-environment interactions, using molecular epidemiological 

research. 

■ Support efforts to synthesize the research, and its implications for future directions, 

with respect to the role of sociocultural, behavioral, emotional, and spiritual factors in 

survivor and family outcomes and their willingness to adopt appropriate surveillance 

and health maintenance behaviors post-treatment. 

■ Ensure that efforts to expand our knowledge base, with respect to the impact of cancer and its treatment on survivor’s outcomes, includes attention to diverse cancer sites 

and under-represented groups — e.g., certain ethnic groups, persons diagnosed at 65 

or older, older survivors with competing health problems, rural populations, lowincome groups, or those with limited education. 

2. Accelerate the pace of intervention research in order to reduce $12.00 M 

cancer-related chronic and late morbidity and mortality. 

■ Expand research on the most promising and cost effective medical, behavioral, 

educational, and psychosocial interventions to address cancer patient needs for 

improved quality of life — e.g., reducing cancer-related symptoms such as distress, 

pain, and nausea; minimizing post-treatment organ dysfunction; promoting healthy 

practices such as exercise, smoking cessation, diet change; and addressing individual 

needs. This research would include examination of the impact on the patient of type, 

intensity, and length of well characterized and controlled interventions on appropriate 

intermediate biomarkers — e.g., immune functioning, cortisol levels, PSA levels. 

$9.00 M 

■ Support the development of interventions that involve family members and friends 

versus those directed only at the cancer survivors, as well as interventions that target 

minority and medically underserved populations. 

3. Develop tools to assess the quality of life and care of post­ $ 5.50 M 

treatment cancer survivors and their family members. 

■ Promote the development of new instruments to assess health-related quality of life 

beyond the active treatment period and evaluate the validity of existing instruments. 

Improving T

$3.00 M 

$5.00 M 

(See page 50, Objective 1.) 

$1.50 M 

$3.00 M 
ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

A Plan and Budget Proposal for Fiscal Year 2004 91

This should include efforts to accelerate the pace of development of common 

toxicity criteria for late effects of cancer treatment. 

■ Promote the development and testing of screening tools that identify individuals 

who are at high risk for poor physical, psychosocial, or behavioral outcomes and 

assess the impact of such screening on patterns and outcomes of care. 

■ Use applied and theoretical statistics to: f scores needed to qualify a change in function as clinically significant — e.g., improvement, 

impairment — and examine the value placed on aspects of quality of health by survivors across the continuum of care. 

■ In collaboration with other NIH institutes (e.g., the National Institute on Aging or 

the National Heart, Lung, and Blood Institute), develop measures that permit the 

evaluation of co-morbidities that are both cancer and non-cancer related. 

4. Enhance NCI’s capacity to track outcomes for cancer survivors. $ 5.50 M 

■ Pilot the expansion of data collection on health-related outcomes for survivors in 

selected Surveillance, Epidemiology and End Results registries. 

■ Develop and support the infrastructure for clinical trials groups to follow patients 

long-term (up to 5-10 years post-treatment). 

■ Establish a separate registry for pediatric cancer survivors seen within the pediatric 

clinical trials network. 

5. Ensure the development and dissemination of new interventions $ 

and best practices, in collaboration with other Federal and healthor cancer-related professional and non-profit organizations. 

■ Promote the development and dissemination of best practice guidelines for followup care, surveillance, and monitoring of cancer survivors who have completed initial 

cancer treatment. 

■ Support studies to test the adoption and impact of best practices in post-treatment 

care of survivors. 

■ Develop and disseminate curricula and standards for the delivery of effective 

psychosocial and supportive care across the illness continuum. 

6. Expand the scientific base for understanding the biologic and $ 

physiologic mechanisms in the adverse late effects of current 

and new cancer treatments. 

■ Fund pre-clinical studies in clinically relevant tissue and animal models to examine 

the incidence of and mechanisms for certain physiologic late effects of cancer treatment (e.g., fatigue, organ dysfunction, second malignancies) and test novel strategies 

to modulate treatment-related toxicities. $3.00 M 

■ Support research that seeks to: investigate the neuropsychologic impact of cancer 

therapy — e.g., mechanisms underlying post-chemotherapy cognitive dysfunction; 

examine chemotherapy induced organ dysfunction — e.g., mechanisms 

underlying cardiac sequelae of doxorubicin treatment; explore the mechanisms of 

delayed radiation induced organ fibrosis and dysfunction; and explore long-term 

immunologic effects of cancer and cancer treatment. 

Management and Support $ 1.00 M 

Total $46.00 M 

$2.00 M 

$2.00 M 

establish the criteria or cutof

$0.50 M 

$1.00 M 

$1.00 M 

$2.00 M 

$2.50 M 

3.50 M 

$1.25 M 

$1.50 M 

$0.75 M 

9.00 M 

$6.00 M 
92 The Nation’s Investment in Cancer Research 

Highlights of Recent Cancer Survivorship Related Research 3 

Tool Enhances Studies on the Long-Term Consequences of Cancer Treatment. Among the critical issues for 

cancer survivors are the “late effects” of their illness and treatment that sometimes do not show up for a number of years. 

To better define these consequences, the NCI is funding a program to update the common toxicity scoring system to 

incorporate the LENT score, Late Effects of Normal Tissues. This scoring system enables investigators to: 

■ Compare newer treatments with the current regimens for treating all cancers. 

■ Relate laboratory research to the severity of effects experienced by patients when investigating 

molecular mechanisms for late tissue damage. 

■ Facilitate the development, for use in clinical trials, of interventions to prevent, reduce, or possbly 

reverse “late effects” of cancer treatment. 

Adjusting Chemotherapy Dosage Reduces Incidence of Congestive Heart Failure among Cancer Survivors. 

Treatment with the chemotherapy drug anthracycline, or more specifically its metabolic byproduct doxorubicin, places survivors at risk for congestive heart failure following their cancer treatment. At greatest risk are women, African Americans, 

and younger patients. NCI-supported researchers have discovered that moderately reducing the overall cumulative dosage 

of anthracycline can reduce the incidence of congestive heart failure from seven to well under one percent. 

Growth Hormone Replacement Helps Children Safely Achieve Normal Height following Treatment for Leukemia. 

Seventy to eighty percent of children with Acute Lymphoblastic Leukemia are cured with current treatments. However, 

because of treatment-related effects, many of these survivors are short in stature as adults. Some of these patients have 

been treated with growth hormone therapy over the years, although the medical community has not been in agreement 

about the effectiveness or the safety of such treatment. An NCI-sponsored team of investigators recently found that replacing growth hormones, in those survivors where it is low, effectively induces “catch-up growth” and most patients reach normal, or near normal, adult heights. This study also examined safety issues, confirming that this treatment does not cause 

relapse or second cancers. Although further study is warranted, these results suggest that growth hormone therapy is a 

safe treatment choice that will benefit many adult survivors of this disease. 

Lung Cancer Survivors Retain Quality of Life. Although lung cancer is one of the most common cancers in the United 

States, little is known about the quality of life of lung cancer survivors. NCI-supported scientists recently analyzed selfreported indicators from five-year survivors of non-small cell lung cancer for factors that have the most effect on quality of 

life, such as other diseases, pulmonary function, depression and anxiety, tobacco use, social and spiritual well-being, and 

demographics. Notably, half of the survivors said their cancer had made a positive change in their life and the majority were 

“very hopeful.” Risk factors for poorer quality of life are strongly linked to depression, suggesting potential interventions by 

health care providers. The number of comorbid conditions (other diseases) experienced by the survivors was a weak indicator of overall life quality, although those with higher income and with few comorbid conditions reported better physical well 

being. Nonwhite participants rated greater than whites for overall quality of life as well as for mental health. , for 

the first time, highlights the range of experiences for long-term survivors of this disease and provides insights for potential 

rehabilitation. The complex interactions of quality of life by race/ethnicity and socioeconomic status deserve further study. 

Social Interventions Can Benefit Breast Cancer Survivors. An NCI-sponsored study of breast cancer survivors over 

a four-year follow-up period shows that health-related quality of life is influenced by the survivor’s availability of social 

networks. On average, socially isolated women were more adversely affected by breast cancer, scoring lower on 

“role function,” “vitality,” and “physical function,” compared to the most socially integrated women. The level of a patient’s 

social integration is an important factor and appears to explain more of this variance than differences in treatment or 

tumor type. The study results suggest that rehabilitation programs should incorporate interventions that address the 

availability of adequate social support among breast cancer survivors. 

3 See also Highlights of Progress, pages 12-13. 

This study
A Plan and Budget Proposal for Fiscal Year 2004 93

I had leukemia as a kid. 

The treatment was rough, but 

my family and friends and all 

of the doctors and nurses really 

helped me keep a positive frame 

of mind — even when the 

cancer came back a few years 

later and I had to go through 

treatment all over again. 

I know I’m fortunate to be alive. 

Adult Survivors of Childhood Cancers 

People’s Story 

An estimated 8.9 million Americans with a history of cancer other than non-melanoma skin cancer or in 

situ diseases were alive in 1997. Of these, an estimated 270,000 were survivors of childhood cancers. 

Survival rates from childhood cancers have increased dramatically over the past few decades, due in 

large part to the fact that nearly 80 percent of children with cancer are treated in clinical trials by multispecialty medical teams. 

For an increasing number of 

patients of all ages, cancer is a 

chronic disease, not a fatal one. 

Over many years of survival, 

patients may find their cancer 

journey marked by a series of 

successes and failures that may 

include the management of 

recurrences, physical and cognitive side effects, or even second 

cancers. As treatments and supportive care have improved, however, it has become possible to 

reduce recurrences and minimize 

or eliminate some of the delayed 

or long-term side effects commonly experienced by patients 

treated with less advanced 

therapies. 

As I’ve gotten older, I’ve needed to 

keep that positive attitude. I’ve had 

some side effects from my treatment 

— I’m diabetic and my heart and 

lung functions are reduced somewhat. 

But I take my medicine, and pay 

attention to my diet, my stress level, 

and things like that. I think that taking good care of myself will help keep 

me cancer free and help me have the 

fullest possible life. 

We recognize more and more that 

surviving cancer involves factors 

related to the way our bodies and 

minds respond to the changes 

brought on by the disease. We 

need to better understand these 

changes and how they influence 

cancer progression, treatment, 

and life after treatment. For 

example, evidence is emerging 

that psychosocial factors that 

influence immune or endocrine 

processes may influence the 

development or progression of 

certain cancers. 

NCI supports research on the 

relationship of particular treatments to specific short- and longterm side effects. We also need to 

understand, for example, the biological basis of these side effects, 

why some patients are able to be 

more optimistic than others about 

treatment success (even in the 

face of a difficult prognosis), and 

what contributes to people’s 

ability to overcome side effects 

that impact their mobility, physical comfort, or psychological well 

being. 

I still check in from time to time with 

the doctors who treated me, but since 

I became an adult, most of my health 

care is provided by my primary care 

physician. 

Because the large and growing 

number of long-term survivors is 

a relatively recent phenomenon, 

no clearly defined system exists 

for monitoring and managing 

long-term and delayed side 

effects or second cancers. 

Research is needed to determine 

the most appropriate roles of 

oncology specialists, primary 

care providers, and survivors 

themselves in their lifelong 

follow-up care. 

PEOPLE’S STOR Y 
Extraordinary Opportunity for Investment 

Research on Tobacco and 

Tobacco-Related Cancers 

The Opportunity 

Lung cancer, the leading cause of cancer death,


would be a rare disease in the absence of smoking.


Smoking is the leading cause of cancers of the lung,


mouth, larynx, esophagus, and bladder, and plays a


role in cancers of the pancreas, cervix, and kidney.


The devastating impact of tobacco use and tobacco


smoke exposure on the incidence of cancer, heart


and lung disease, stroke, and other serious illnesses


is both compelling and conclusive. Tobacco use


causes more premature deaths (approximately


430,000 per year in the United States) than do all


drugs of abuse combined. In 2002, about 170,000


people will die of cancer because of their use of


tobacco products. A major challenge in the fight


against tobacco-related cancers is that addiction to


nicotine drives the continued use of tobacco even


when the user is fully aware of increased risk of dis­


ease and premature death. Some people will contin­


ue to smoke even as they undergo treatment for a


life threatening disease. 


NCI’s commitment to preventing, diagnosing, and


treating tobacco-related cancers began more than 


40 years ago. To remain at the leading edge of this


important area of research, NCI must devote addi­


tional resources to address the complex challenges


of tobacco use. Research recommendations related


to tobacco use made by NCI’s Lung Cancer


Progress Review Group echo many of the 


Institute’s priorities, such as: 


■ Developing and expanding new approaches to


the biology and treatment of nicotine addiction. 

■	 Conducting basic biological research on the 

effects of tobacco exposures including the differential toxicity of various tobacco products. 

■ Continuing and evaluating current and planned 

population-based tobacco control efforts. 

■ Detecting and treating tobacco-related cancers 

and metastatic disease. 

GOAL 

Understand the causes of 

tobacco use, addiction, 

and tobacco-related 

cancers and apply this 

knowledge to their prevention and treatment. 

NCI also has a special concern for the health of 

former smokers who, despite quitting, now comprise about half of those diagnosed with lung 

cancer. The development and marketing of new 

tobacco products also is of great concern. Scientists 

must examine the toxicity of these products as well 

as evaluate whether or not “harm reduction” is a 

viable public health strategy. NCI’s commitment to 

research on tobacco and tobacco-related cancers is 

reflected in our investments both in basic biological 

research on the effects of tobacco exposures and in 

community-based studies of smoking prevention 

and cessation programs. 

Progress in Pursuit of Our Goal 

Defining Biological, Behavioral, and 

Social Bases of Tobacco Use and 

Addiction 

NCI is advancing tobacco research to answer questions related to why people begin to use tobacco, 

become addicted, and have difficulty stopping use 

of tobacco products, as well as genetic and environmental factors that influence tobacco use and addiction. 

Funding for Transdisciplinary Tobacco Use 

Research Centers (TTURCs), located within 

seven academic institutions, is approaching its 

fourth year of sponsorship by NCI, the National 

Institute on Drug Abuse (NIDA), and the Robert 

Wood Johnson Foundation. These centers are supporting a broad array of studies, including projects 

evaluating new models of nicotine addiction, the 

role of genetic and environmental factors in smoking initiation and persistence, methods for preventing tobacco use across cultures, and determinants of 

relapse. TTURC sponsored research continues to 

inform us. 

■ Certain genes regulating the activity of the neurotransmitter dopamine help determine which 

smokers are able to quit. Although these genes 

do not appear to influence the effectiveness of 

94 The Nation’s Investment in Cancer Research 
the medication bupropion, another gene 

involved in drug metabolism did predict 

therapeutic response to treatment. 

■	 Older adolescence, peer smoking, cigarette 

availability, depression, delinquency, and alcohol 

use are factors that influence smoking progression in youth. Investigators also found that prenatal exposure to nicotine increases the likelihood that a smoker will progress to regular use. 

This information is being used to develop cessation programs for high-risk adolescents. 

■	 There are links between specific personality traits 

and early initiation of smoking. Teenagers with a 

combination of aggressive and depressive characteristics are at an elevated risk for cigarette smoking. Moreover, depressed adolescents who are 

highly receptive to tobacco advertising are also 

at higher risk. These findings lead researchers to 

believe that tailoring prevention and intervention 

efforts to encompass these factors could lead to 

a reduction in youth smoking. 

NCI supports 50 research projects related to the 

prevention and cessation of tobacco use by 

children and youth. Studies reveal that adolescent smokers can experience withdrawal symptoms 

within one month of smoking initiation. A recently 

published study showed that not all tobacco 

dependence in youth is physiological, but that psychological determinants of dependence are equally 

significant. The authors of this study offered a theory whereby loss of autonomy signals onset of 

dependence. Loss of autonomy occurs when either 

the physical or psychological effects of nicotine present a barrier to quitting. Their work resulted in the 

International Activities 

“Hooked on Nicotine Checklist,” a self-administered 

questionnaire that helps smokers identify ten warning signs of nicotine addiction. This measure offers 

a validated, theoretically based tool that measures 

tobacco dependence. 

Results from a recent study of prevalence and 

predictors of tobacco use among Asian 

Americans highlights the need for culturally tailored prevention, cessation, and treatment interventions. Investigators collected data on 1174 Chinese, 

Korean, Vietnamese, and Cambodian respondents in 

the Delaware Valley Region of the United States 

and found that 40.2 percent of respondents had a 

history of tobacco use and 29.6 percent were current 

users. Men were more likely than women to smoke, 

and there were significant differences among never 

smokers, current smokers, and ex-smokers by sex, 

ethnicity, educational attainment, and marital status. 

Preventing and Treating Tobacco Use 

and Tobacco-Related Cancers 

Research supported through TTURCs, the State 

and Community Tobacco Control Intervention initiative, and several of the youth and tobacco 

research projects is producing important new 

insights and knowledge about the social, biobehavioral, and genetic factors that influence tobacco use 

and addiction in youth and adults. To complement 

these efforts, NCI and NIDA initiated a Working 

Group on Medication Development for 

Nicotine Addiction that explores ways to draw 

upon NIDA’s expertise in addiction research as well 

as NCI’s experience in drug development. 

In 2002, NCI opened the doors to the Tobacco 

95 ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

The World Health Organization (WHO) estimates that four million people die each year worldwide from 

tobacco-related illness, and if current trends continue, this figure will rise to about 10 million per year by 

2030, with 70 percent of those deaths occurring in the developing world. 

Examples of NCI support of global tobacco research include: 

■	 Jointly sponsoring the Symposium on Tobacco-Related Cancers with the Japan Society for the 

Promotion of Science, in February 2002, to bring together international researchers to address 

molecular, epidemiology, behavioral, cancer control, and clinical aspects of these cancers. 

■	 Co-hosting the Third International Conference on Smokeless Tobacco, in September 2002, with the 

Centers for Disease Control and Prevention and the Sweden Centre for Tobacco Prevention. 

■	 Providing $1.7 million over the next several years to extend and enhance the research interests of 

U.S. and collaborating foreign scientists and institutions to combat the growing incidence of tobaccorelated illness in the developing world, through the International Tobacco and Health Research and 

Capacity Building program, led by the NIH Fogarty International Center. 

■	 Initiating a multi-institutional, population-based, case-control study of lung cancer and smoking in 

Milan, Italy. This study of 4,500 subjects investigates the genetics of nicotine addiction and lung cancer. 

A Plan and Budget Proposal for Fiscal Year 2004 
96 The Nation’s Investment in Cancer Research 

The Plan 

Research On Tobacco and Tobacco-Related Cancers 

GOAL 

Understand the causes of tobacco use, addiction, and tobacco-related cancers and apply this 

knowledge to their prevention and treatment. 

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004 

1. Expand the infrastructure needed to conduct a vigorous research and $25.50 M 

public health effort consistent with the enormous burden of 

tobacco-related disease. 

■ Initiate prospective observational studies of the quitting and relapse processes, 

including the effectiveness of medications. 

■ Continue support for including tobacco use in the Current Population Survey and 

increasing the number of non-English language translations. 

■ Along with other government and non-government institutions, support the use 

of national, state, and regional tobacco surveillance data and the development of 

analytical tools, resources, and a network to track and evaluate progress in cancer 

control. 

■ Expand the Cancer Intervention and Surveillance Modeling Network (CISNET) to 

develop models of tobacco use, dependence, relapse, and disease development. 

■ Renew and expand support for the Transdisciplinary Tobacco Use Research Centers 

program, in collaboration with relevant public and private organizations. 

■ Adopt and apply integrated study design models such as BEGIN (Behavior, 

Exposure, Genetics, Intermediate biomarkers, and Neoplastic markers) to support 

an interdisciplinary integrated approach to tobacco-related research. 

2. Support innovative, integrated investigations to understand and $ 19.00 M 

treat tobacco use and addiction. 

■ Capitalize on the breadth of expertise across NIH Institutes by supporting 

collaborative projects at NCI’s new tobacco use research clinic. 

■ Accelerate the identification of new treatments for nicotine addiction through the 

implementation of a drug development and clinical trials collaborative group by NCI 

and other NIH institutes. 

■ Support research on smoking cessation and relapse prevention in cancer patients and 

survivors. 

Intervention Research Clinic, a state-of-the-science center for tobacco use research by NCI scientists and collaborators, including those in the NCI 

and other NIH intramural programs. The clinic will 

be a resource for NIH scientists conducting a range 

of genetic, epidemiological, basic science, and 

behavioral research studies and could provide 

research-based tobacco cessation services to patients 

from the NIH community. 

Translating Research Into Improved Outcomes 

is an initiative that offers funding opportunities to 

current NCI-funded investigators to support critical 

dissemination of promising interventions in the 

field of tobacco use and other cancer control areas. 

NCI is also actively involved in a public-private collaborative effort to develop a National Blueprint for 

Disseminating and Implementing Evidenced-Based 

Clinical and Community Strategies to Promote 

Tobacco-Use Cessation. 

$4.00 M 

$2.50 M 

$2.00 M 

$2.00 M 

$15.00 M 

$1.00 M 

$4.00 M 

$2.00 M 
ADDRESSING AREAS OF PUBLIC HEAL TH EMPHASIS 

A Plan and Budget Proposal for Fiscal Year 2004 97

■ Support the identification, development, and dissemination of effective tobacco use, 

prevention, and cessation interventions to underserved populations. 

■ Provide supplements to further our understanding of disparities in patterns of tobacco use, cessation, and relapse. 

■ Collaborate with the Centers for Disease Control and Prevention and other relevant 

public and private organizations to develop integrated and coordinated communication 

efforts focused on tobacco use and cessation, including Internet strategies. 

■ Support innovative, population-based studies involving a whole genome approach to 

elucidate the genetics of smoking, in collaboration with other NIH institutes and 

centers. 

3. Apply cutting-edge research to better understand and treat $ 31.00 M 

tobacco-related cancers. 

■ Support clinical and population studies that include tissue and biospecimen 

resources to investigate the genetic, biological, and behavioral factors influencing 

vulnerability to smoking dependence and tobacco-related cancer. 

■ Support studies of the mechanisms of susceptibility to tobacco-related cancers to 

understand the nature and implications of tobacco products intended to reduce 

harm. 

■ Provide supplements to address disparities in clinical care of tobacco-related cancers. 

$3.00 M 

■ Support interdisciplinary studies to accelerate development of new, molecularly 

based lung cancer treatments. 

■ Enhance the Cancer Information Service’s smoking cessation services and research 

infrastructure to improve treatment of tobacco use. 

Management and Support $ 

Total $76.00 M 

NCI is funding preclinical and clinical studies to 

identify newer, more potent agents that may 

prevent cancers in former smokers. 

clinical studies focus on validating surrogate biomarkers1 for tobacco-related cancers in animal models under experimental protocols that mimic the 

high-risk smoker. These studies will identify and 

prioritize agents that prevent cancers in tobaccosusceptible organ systems. The clinical research 

initiative is supporting four clinical trials evaluating 

the efficacy of chemopreventive agents in specified 

cohorts of former smokers. A variety of novel biomarkers as well as imaging modalities, such as the 

spiral computed tomography (CT) scan, are being 

examined with regard to their potential utility in 

chemopreventive studies. 

NCI is also supporting the National Lung Cancer 

Screening Study to assess the feasibility of spiral 

CT to detect early lung cancers.2 

1 A surrogate biomarker is a measurable molecular feature (for example, a blood protein) that can be used to monitor the course of a disease or the effects 

of treatment in place of more long-term outcome measures, such as time to tumor progression, remission, or death. 

2 See page 69. 

$3.00 M 

$3.00 M 

$1.00 M 

$5.00 M 

$6.00 M 

$10.00 M 

$10.00 M 

$2.00 M 

0.50 M 

The pre-
Public and Private Partnerships and Collaborations 

In support of tobacco research collaborative efforts, NCI is: 

■	 Supporting seven Transdisciplinary Tobacco Use Research Centers in partnership with the National 

Institute on Drug Abuse (NIDA) and the Robert Wood Johnson (RWJ) Foundation to integrate 

tobacco-related research on genetic susceptibility, sociocultural factors, innovative treatments, and 

healthcare policy. 

■	 Facilitating an NCI/NIDA Working Group on Medication Development for Nicotine Addiction to 

develop targeted new treatments. 

■	 Partnering with 10 other public and private organizations to develop a “National Blueprint for 

Disseminating and Implementing Evidence-Based Clinical and Community Strategies to Promote 

Tobacco-Use Cessation.” 

■	 Organizing and sponsoring a Women, Tobacco, and Cancer Conference with the NIH Office of 

Research on Women’s Health, the DHHS Office of Women’s Health, the American Cancer Society, 

the American Legacy Foundation, and others. 

■	 Sponsoring a National Tobacco Monitoring Research and Evaluation Workshop, in November 2002, 

along with the Centers for Disease Control and Prevention, RWJ Foundation, and American Legacy 

Foundation, to improve the utility of tobacco use surveillance systems. 

■	 Participating in NOTURF (National Organization for Tobacco Use Research Funders), a consortium 

of research funding organizations in the United States and Canada dedicated to fostering communication and action around tobacco research. 

Understanding the Interplay Among 

Tobacco, Other Exposures, and Cancer 

NCI is pursuing research opportunities to better 

understand the interplay among tobacco and other 

exposures such as alcohol and radon, and a person’s 

cancer risk. This work involves resource intensive, 

longitudinal, screening, and cohort studies that may 

involve genetic and biomarker components from 

tissue, blood, urine, sputum, and other body fluids. 

Several studies within the Prostate, Lung, 

Colorectal, and Ovarian (PLCO) screening trials 

are specifically focusing on tobacco exposure and 

cancer. These studies are examining the relationship between tobacco and colon adenomas, a comparison of patients with emphysema, and a control 

group (persons without cancer or related symptoms) 

to identify genetic factors that may influence susceptibility to this condition. Another investigation 

will target current and former smokers to identify 

candidate genes thought to influence smoking. 

The Cohort Consortium,

3 a group of investigators 

involved in separate prospective studies of large 

population groups, will expand their investigation 

beyond looking at breast and prostate cancer to 

identifying and studying tobacco-related cancers. 

These researchers will investigate a rare subtype 

of lung adenocarcinoma; lung cancer in young people, non-smokers, and families; and rarer tobaccorelated tumors such as pancreas and nasal sinuses. 

Efforts are underway to collect tissue from a 

broader group of PLCO participants to allow high 

throughput analysis of new markers of patients 

with specific cancers. 

Additional relevant studies are yielding information 

on cancer risk related to the interplay among 

tobacco and other exposures. In a case-control 

interview study on patients with esophageal cancer, 

researchers found a three-fold excess risk for the 

disease among those in the highest quartile of body 

mass index, a predisposition of obese individuals to 

gastroesophageal reflux disease, and an association 

between esophageal cancer and cigarette smoking, 

with little reduction in risk until 30 years after 

smoking cessation. A large case-control study 

of bladder cancer is ongoing in the New England 

region of the United States and Spain to identify 

occupational bladder carcinogens and to evaluate 

cigarette smoking (black vs. blond tobacco in Spain) 

as well as phenacetin-containing analgesics, dietary 

factors, urination frequency, and pH. Genetic susceptibility markers will be evaluated in relation to 

bladder cancer risk as well as their interaction with 

environmental, occupational, and tobacco risk factors. 

98 

3 See page 49. 

The Nation’s Investment in Cancer Research 
A Plan and Budget Proposal for Fiscal Year 2004

Index of Selected Topics* 

aging and cancer, 8, 12, 21, 46-47, 77, 79, 88, 90


alcohol and cancer, 23, 49, 53, 95, 98


bladder cancer, 19, 22, 53, 63, 94, 98


blood system cancers, 20. See also leukemia, lymphoma,


myeloma. 

brain tumors, 15, 19, 20, 21, 32, 35, 68, 69, 88 

breast cancer, 8, 9, 10, 11, 12, 15, 16, 19, 20, 22, 32, 37, 49, 

50, 51, 52, 53, 54, 59, 61, 63, 64, 66, 69, 71, 72, 74, 76, 79, 

81, 82, 85, 86, 88, 92, 98 

cervical cancer, 8, 11, 13, 17, 53, 64, 68, 82, 84, 85, 86, 94 

chemotherapy, prevention and treatment, 11, 15, 37, 64, 

69, 73, 82, 88, 91, 92, 97. See also targeted therapy. 

childhood cancers, 12, 13, 21, 37, 44, 45, 61, 88, 91, 92, 93, 

95 

colorectal cancers, 8, 9-10, 11, 16, 17, 19, 35, 36, 37, 40, 49, 

51, 52, 53, 59, 63, 66, 68, 69, 79, 82, 85, 98 

diet and cancer, 8, 16, 21, 23, 40, 52, 53, 64, 72, 73, 75, 76, 

83, 85, 90, 93, 98 

endometrial cancer, 53 

esophageal cancer, 19, 23, 53, 94, 98 

Ewing tumors, 45 

exercise and cancer, 8, 53, 90 

gastrointestinal cancers, 32, 35, 36, 37, 68. See also colorectal cancers, gastrointestinal stromal tumors, stomach cancer. 

gastrointestinal stromal tumors, 37, 68 

gene expression array, 54 

genitourinary cancers, 20, 32. See also prostate cancer. 

genomics, 15, 17, 18, 42, 43, 49, 51, 53, 61, 64 

gynecologic cancers, 18, 19, 20. See also cervical cancer, 

endometrial cancer, ovarian cancer. 

head and neck cancer, 20, 33, 35, 63. See also laryngeal cancer, mouth cancer, oral cancers, pharyngeal cancer, 

supraglottic cancer. 

immune system and cancer, 10, 56, 60, 64, 70, 86, 90, 91, 

93. See also vaccines and cancer. 

kidney cancer, 11, 17, 19, 22, 53, 71, 94 

laryngeal cancer, 53, 94 

leukemia, 10, 13, 17, 19, 20, 21, 35, 36-37, 44, 54, 64, 71, 

92, 93 

liver cancer, 53 

lung cancer, 8, 10, 11, 13, 18-19, 20, 33, 35, 50, 53, 54, 59, 

63, 67, 68, 69, 71, 79, 85, 92, 94-98. See also tobacco and 

cancer. 

lymphoma, 10, 12, 15, 17, 19, 20, 21, 33, 35, 44, 45, 52, 54, 

63, 70-71, 88 

melanoma, 10, 17, 53, 63, 71. See also skin cancers. 

mesothelioma, 11 

microenvironment. See tumor microenvironment. 

minorities and cancer, 4, 8-9, 12-13, 16-17, 22, 23, 31, 33, 

39, 75, 76, 77, 79, 81, 83, 84-87, 90, 92, 95, 97 

molecular profiling of genes and proteins, 9, 20, 49, 52, 54, 

56, 59, 60. See also gene expression array, proteomics. 

molecular targets. See targeted interventions. 

mouth cancer, 53, 94 

myeloma, 19, 20, 21, 63, 71 

nanotechnology, 15, 56, 65, 69 

nervous system cancers, 20 

neuroblastoma, 45, 61, 71 

neuroendocrine cancers, 71 

oral cancers, 59 

ovarian cancer, 9, 10, 15, 20, 33, 35, 45, 52, 54, 59, 69, 79, 

82, 98 

pancreatic cancer, 9, 11, 12, 19, 20, 21, 32, 51, 52, 61, 63, 

94, 98 

pharyngeal cancer, 53 

progress review groups, 16, 18-23, 27, 29, 30, 60, 68, 94 

prostate cancer, 9-13, 15, 19, 20, 22, 33, 35, 40, 50, 51, 52, 

53, 54, 58, 59, 61, 63, 66, 68, 71, 79, 82, 85, 98 

proteomics, 14, 15, 17, 18, 22, 28, 45, 54, 57, 58, 59, 62, 64. 

See also molecular profiling of genes and proteins. 

radiation therapy, 13, 21, 36, 47, 61, 63, 64, 65, 67, 69, 73, 

79, 85, 91 

rhabdomyosarcoma, 45 

sarcomas, 20, 71. See also rhabdomyosarcoma. 

skin cancers, 20, 33, 35. See also melanoma. 

socioeconomic status and cancer, 13, 79, 85, 86, 92 

stomach cancer, 13, 19, 20, 23, 53 

supraglottic cancer, 68 

surgery, 10, 13, 15, 22, 36, 47, 59, 65, 69, 82 

targeted interventions, 5, 9-11, 13, 15, 17, 20, 22, 30, 33, 

36-41, 44, 47, 48, 54, 57, 58, 59, 60-64, 91 

testicular cancer, 52 

tobacco and cancer, 8-9, 17, 19, 21, 22, 23, 33, 35, 49, 53, 

69, 72, 73, 77, 83, 85, 90, 92, 94-98 

tumor microenvironment, 5, 12, 14, 19, 20, 30, 46, 48, 56-59 

vaccines and cancer, 17, 61, 63, 64. See also immune system 

and cancer. 

99 

* See also Table of Contents on page 2 for major topics covered in this document. 

INDEX OF SELECTED TOPICS 

A Plan and Budget Proposal for Fiscal Year 2004 
The Nation’s Investment in Cancer Research 

Acknowledgments 

The following people at NCI deserve special recognition 

for their contributions to the development of this document. 

■	 In the Office of Science Planning and Assessment: 

Cherie Nichols, Kathie Reed, Jane Lockmuller, 

Kathy Sorrow, Marianne Kost, Bernard Glassman, 

Anne Tatem, Lisa Stevens, Samir Sauma, and D. J. Joya 

■	 NCI Priority Area Champions: Jeff Abrams, Rachel 

Ballard-Barbash, J. Carl Barrett, Martin Brown, Kenneth 

Buetow, Neil Caporaso, Michaele Christian, Norman 

Coleman, Robert Croyle, Brenda Edwards, Ellen 

Feigal, Harold Freeman, Robert Hiatt, Robert Hoover, 

Marvin Kalt, Jon Kerner, Brian Kimes, Gary Kreps, 

Scott Leischow, Joseph Lipscomb, Mary McCabe, 

Lori Minasian, Ed Monachino, Barbara Rimer, Julia 

Rowland, Edward Sausville, Dinah Singer, John Sogn, 

Robert Strausberg, and Daniel Sullivan 

■	 In the Office of Budget and Financial 

Management: Jim Dickens and Ngan Nguyen 

■	 In other NCI Offices and Programs: Jill Johnson, 

John Hartinger, Donna Bonner, Donna Kerrigan, 

Jim Mathews, and Paul LaMasters 

Other contributors at NCI included Alan Rabson,


Joseph Fraumeni, Peter Greenwald, Kelly Blake, 


Kevin Callahan, Buddy Clark, Larry Clark, Jim Corrigan,


Barbara Croft, Andrea Denicoff, Marilyn Duncan, Kay


Flemming, Leslie Ford, Barbara Galen, Louise Grochow,


Ernie Hawk, John Hoffman, Jim Jacobson, Gary Kelloff,


Elaine Lee, Allison Linden, Lance Liotta, Cheryl Marks,


Susan McCarthy, Anne Menkens, Julie Schneider, 


Kara Smigel-Croker, Sudhir Srivastava, Tracy Thompson,


Stacey Vandor, and Paula Zeller. 


The following people and organizations outside of NCI 

reviewed and provided input to the draft document in the 

summer of 2002. 

■	 NCI Advisory Groups: National Cancer Advisory 

Board member Ralph S. Freedman; Board of Scientific 

Advisors member Nancy Mueller; Board of Scientific 

Counselors members Elizabeth Fontham, Laurence N. 

Kolonel, and Alice Pentland; Director’s Consumer Liaison 

Group members Kathy Giusti, Paula Kim, Barbara 

LeStage, Gena Love, Karen Packer, Christopher G. Pablo, 

Henry Porterfield, Nyrvah Richard, and Doug Ulman; 

and Progress Review Group leaders Scott Kern and 

Nicole Urban 

■	 Cancer Centers and SPOREs: H. Shelton Earp, 

Jane Ehrke, Stephen P. Goff, Lynn Matrisian, Edward 

Partridge, and Kent Lloyd 

■	 Professional and Advocacy Organizations: 

Alliance for Prostate Cancer Prevention, American 

Association for Cancer Research, American Public 

Health Association, American Society for Clinical 

Oncology, American Society for Therapeutic Radiology 

and Oncology, The Children’s Cause, Lymphoma 

Research Foundation, National Coalition for Cancer 

Survivorship, North American Brain Tumor Coalition, 

Oncology Nursing Society, Robert Wood Johnson 

Foundation, and Susan G. Komen Breast Cancer 

Foundation 

■	 Other Reviewers: Martin Hauer-Jensen, Deborah 

Mayer, Stephen Taplin, and Clare MC Tempany 

■	 HHS Agencies: National Institute on Aging and the 

Centers for Disease Control and Prevention 

And special thank you’s go to Suzanne Reuben of 

Progressive Health Systems, Sharyn Horowitz of Analytical 

Sciences, Inc., Rosemary Yancik of the National Institute on 

Aging, and Lynne Komai of The Watermark Design Office. 

100 The Nation’s Investment in Cancer Research 
The Nation’s Investment in Cancer Research 

. . . valuable rewards in cancer signatures research. 

By establishing the “Signatures of Cancer” as a major priority area six years ago, NCI recognized that the cancer field faced an “extraordinary opportunity” that could revolutionize 

cancer detection and diagnosis. 

that every cell has a molecular signature — a unique biological characteristic that is related 

to the cell’s function in the body. Even more intriguing was the discovery that as a cell 

transforms from normal to malignant, its signature changes, and this change is a signal 

of the presence of cancer. We realized that by accurately “reading” the changes that 

distinguish a cancer cell from its normal counterpart, we could create tools to detect the 

earliest signature changes of cancer; enhance diagnosis by identifying a tumor according to 

its molecular features; and advance prevention and treatment by developing interventions 

that target the molecular features of a tumor. By committing the exceptional resources 

and developing the innovative new research programs needed to enable creative and high 

quality signatures research, we are able, today, to demonstrate how our Nation’s investment 

in cancer research is rendering dramatic changes in cancer prevention and care. 

Through several ambitious initiatives, investigators are making striking progress in: 

Defining the Signatures of Cancer Cells. Since 1997, Cancer Genome Anatomy 

Project (CGAP) scientists have worked to uncover all of the molecular information in a 

cancer cell and its components, including proteins. Today, they have successfully built a 

nearly complete tumor gene index by identifying over a million genes in more than 

40 tissues. Building on this effort, researchers are annotating the types of cells and cancer 

that express these genes, developing catalogues of chromosomal changes in cancer, and 

identifying common genetic variations that influence cancer risk in various populations. 

Identifying Biomarkers for Early Detection. Launched in 1999, the Early 

Detection Research Network (EDRN) aims to use the wealth of information coming from 

CGAP in the development of cancer biomarkers. Through this national research forum, 

scientists are working to discover, develop, and validate early markers of cancer. EDRN 

scientists already have successfully discovered a number of biomarkers that allow for the 

earlier detection of breast, prostate, colon, lung, and other cancers. NCI and EDRN 

scientists also have effectively applied proteomics to develop a potential screening test 

that uses patterns of proteins (see picture) to detect ovarian cancer. 

Better Distinguishing Different Types of Cancer. The Director’s Challenge: 

Toward a Molecular Classification of Tumors was established in 1999 to support investigators in their efforts to apply gene- and protein-based strategies in the development of new 

molecular classification schemes for human cancers. This information will improve our 

ability to accurately classify and diagnose cancer, predict prognosis, and select targeted 

treatments. Already, these studies are revealing new types and subtypes of cancer that 

appear to predict which patients will respond to particular therapies. Microarrays 

(see picture) are helping scientists identify tumor subtypes based on differences in 

gene expression. 

For more information on NCI’s cancer signatures research, go to plan.cancer.gov. 

Studies of the molecular underpinnings of cancer revealed 
NATIONAL INSTITUTES OF HEALTH 

U. S. Department of Health and Human Services 

NIH Publication No. 03-4373 

October 2002 T290 

Ordering this document 

By email cisocc@pop.nci.nih.gov 

By Internet cancer.gov/publications 

By phone 1-800-4-cancer 

By fax 1-301-330-7968 

Valuable World Wide Web Locations 

National Cancer Institute cancer.gov 

National Institutes of Health www.nih.gov 

Department of Health and Human Services hhs.gov 

Cancer News newscenter.cancer.gov 

Cancer Science newscenter.cancer.gov/sciencebehind 

Cancer Information Service (CIS) 

By phone 

1-800-4-CANCER (1-800-422-6237) 

For deaf and hard of hearing 

On the Web 

From cancer.gov, click on LiveHelp. 

Other Assistance 

Send an email to cancermail@cips.nci.nih.gov to request 

physician services or enter the one-word message “Help” to 

receive a contents list and ordering instructions for NCI 

information via email. 

Search service for physicians 

This Document Online 

Access expanded content for this Plan and Budget Proposal, including links to key Websites, at plan.cancer.gov. 

Online links related to the chapters in this book include the following. 

National Agendas for Disease-Specific Research 

■ Progress Review Groups prg.cancer.gov 

■ Research Initiatives cri.cancer.gov 

Investigator-Initiated Research 

■ Research Portfolio researchportfolio.cancer.gov 

■ Research Resources resresources.nci.nih.gov 

■ Funding cancer.gov/researchfunding 

Centers, Networks, and Consortia 

■ Cancer Centers cancer.gov/cancercenters 

■ SPOREs spores.nci.nih.gov 

National Clinical Trials Program 

■ Cancer Clinical Trials cancer.gov/clinicaltrials and 

cancer.gov/clinicaltrials/understanding 

Bioinformatics for Cancer Research 

■ Center for Bioinformatics ncicb.nci.nih.gov 

Genes and the Environment 

■ Family Registry epi.grants.cancer.gov/CFR 

■ Genetics Network epi.grants.cancer.gov/CGN 

Signatures and Microenvironment 

■ CGAP cgap.nci.nih.gov 

■ EDRN cancer.gov/prevention/cbrg/edrn 

■ Director’s Challenge dc.nci.nih.gov 

Molecular Targets 

■ Developmental Therapeutics dtp.nci.nih.gov 

■ Intramural Initiatives ccr.cancer.gov/initiatives 

Cancer Imaging and Molecular Sensing 

■ Biomedical Imaging cancer.gov/bip and cancer.gov/clinicaltrials/understanding/science-explained-imaging 

Cancer Communications 

■ Extraordinary Opportunity cancercontrol.cancer.gov/eocc 

Quality of Cancer Care 

■ Applied Research appliedresearch.cancer.gov 

Cancer-Related Health Disparities 

■ NCI Center crchd.nci.nih.gov 

Cancer Survivorship 

■ Survivorship Research survivorship.cancer.gov 

Tobacco and Tobacco-Related Cancers 

■ Tobacco Research tobaccocontrol.cancer.gov 

Research Training and Career Development 

■ Opportunities cancertraining.nci.nih.gov 

Emerging Trends in Cancer 

■ Progress Report progressreport.cancer.gov 

■ Mortality Maps cancer.gov/atlasplus 

■ SEER seer.cancer.gov 

Telephone Assistance for Smoking Cessation 

Through the Cancer Information Service (CIS) at 1-800-4-CANCER, 

NCI provides telephone-based assistance for smokers who want to 

quit. Callers in the United States, Puerto Rico, the U.S. Virgin 

Islands, and territories in Guam and Saipan can speak with someone 

in English or Spanish. 

Smoking cessation service representatives: 

■ Assess the caller’s individual smoking behavior. 

■ Provide brief educational messages. 

■ Help callers develop a personalized action plan for quitting. 

■ Reinforce the information with written materials. 

1-800-332-8615 

1-800-345-3300