Progress

Review

Groups

Report of the 

Gynecologic Cancers 

Progress Review Group

November 2001
Report of the Gynecologic Cancers 

Progress Review Group 

November 2001 
From the Leadership 

It is a great pleasure to submit this Report of the Gynecologic Cancers Progress Review Group 

(GYN PRG) to the Acting Director and Advisory Committee to the Director of the National 

Cancer Institute (NCI). At the beginning of 2001, the GYN PRG accepted the charge of NCI 

Director Dr. Richard Klausner to develop a national plan for the next 5 years of gynecologic 

cancer research. The expertise of the GYN PRG members and the clinical, research, industrial and 

advocacy community participants of the GYN PRG Roundtable Meeting met that charge with this 

report. It reflects innovative research strategies that represent the next steps toward preventing, 

diagnosing and treating gynecologic cancers. We look forward to discussing these priorities with 

the leadership of the NCI. 

William J. Hoskins, M.D. Nicole Urban, Sc.D. Edward C. Trimble, M.D. 

PRG Co-Chair PRG Co-Chair PRG Executive Director 

Memorial Sloan-Kettering Fred Hutchinson Cancer National Cancer Institute 

Cancer Center Research Center 
We the undersigned members of the Gynecologic Cancers Progress Review Group concur 

with the enclosed report. 

William J. Hoskins, M.D. 

PRG Co-Chair 

Edward C. Trimble, M.D. 

PRG Executive Director 

Ruedi Aebersold, Ph.D. 

Garnet L. Anderson, Ph.D. 

Renzo Canetta, M.D. 

Mary B. Daly, M.D., Ph.D. 

Michael A. Friedman, M.D. 

Paul Goodfellow, Ph.D. 

Loretta Itri, M.D. 

Nicole Urban, Sc.D. 

PRG Co-Chair 

Ronald Alvarez, M.D. 

Michael J. Birrer, M.D., Ph.D. 

David Cella, Ph.D. 

Mary (Nora) Disis, M.D. 

David M. Gershenson, M.D. 

Hedvig Hricak, M.D., Ph.D. 

Beth Y. Karlan, M.D. 

Douglas R. Lowy, M.D. 
We the undersigned members of the Gynecologic Cancers Progress Review Group concur 

with the enclosed report. 

Cherie Nichols, M.B.A. 

Karl Podratz, M.D., Ph.D. 

Martha C. Romans, B.A. 

Branimir I. Sikic, M.D. 

Jane Weeks, M.D. 

Richard J. Zaino, M.D. 

Samuel Mok, Ph.D. 

Edward Partridge, M.D. 

Marcus E. Randall, M.D. 

Mary Jackson Scroggins, M.A. 

James Tate Thigpen, M.D. 

Stacey Young-McCaughan, R.N., Ph.D. 
Acknowledgments 

This report is the product of 11 months of intense work that drew on the combined expertise and 

efforts of many individuals. The Progress Review Group (PRG) particularly acknowledges the 

contributions of: 

• The many scientists, clinicians, and advocates across the country, who gave of their time and 

knowledge and were an integral part of making this report a successful document that should 

help advance research in gynecologic cancers. 

• Staff of the NCI Office of Science Planning and Assessment (OSPA), under the leadership of 

Cherie Nichols, who provided ongoing guidance and technical support throughout the PRG 

process—in particular, Deborah Duran and Anna T. Levy, who coordinated the PRG, as well 

as Kevin Callahan, James Corrigan, and Annabelle Uy. 

• A group of experienced science writers, who provided excellent writing support both during 

the Roundtable Meeting and the subsequent development of the PRG report: Deborah Shuman, 

Nancy Volkers, Randi Henderson, Alice Lium, Cheryl Pellerin, Barbara Shapiro, and Cheryl 

Ulmer. 

• Josette James, Audrey Thomas, and their colleagues at Palladian Partners, Inc., who provided 

excellent logistical support to the PRG. 

• David N. Louis, Co-Chair of the Brain Tumor Progress Review Group, for his presentation to 

Roundtable participants. 
Table of Contents

Priorities of the Gynecologic Cancers Progress Review Group ..................................................1 

Introduction..................................................................................................................................1 

Background............................................................................................................................1 

Process ...................................................................................................................................1 

Overview of Priorities..................................................................................................................3 

Essential Research Priority ..........................................................................................................4 

The Virtual Shared Specimen Resource ................................................................................4 

High-Impact Research Priorities..................................................................................................7 

Molecular Profiling for Markers of Risk, Early Detection, and Treatment...........................7 

Human Papillomavirus Vaccines.........................................................................................10 

Quality of Life: Disparities Related to Care ........................................................................12 

Scientific Opportunities.............................................................................................................14 

Conclusion .................................................................................................................................16 

Appendix A: About the National Cancer Institute’s Progress Review Groups .......................17 

Appendix B: Gynecologic Cancers PRG Membership Roster ..................................................19 

Appendix C: Gynecologic Cancers PRG Roundtable Participants Roster ..............................21 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups ........25 

Health-Related Quality of Life and Survivorship......................................................................25 

Clinical and Molecular Genetics................................................................................................29 

Defining Signatures of Cancer Cells, Genomics, Proteomics, and Informatics........................32 

Treatment and Drug Discovery..................................................................................................35 

Immunology...............................................................................................................................40 

Radiobiology..............................................................................................................................45 

Laboratory and Clinical Models ................................................................................................54 
Health Disparities, Communication, Education, and Quality of Care.......................................57 

Genes and Environment.............................................................................................................60 

Imaging ......................................................................................................................................67 

Tumor Biology, Hormone Receptors, Epithelial-Stromal Interactions,

and Early Activation ............................................................................................................70 

Angiogenesis, Metastasis, and Growth Signaling......................................................................74 

Early Detection, Screening, and Prevention ..............................................................................81 

Treatment, Clinical Trials, Gene Therapy, Staging, and Surgery..............................................87 

Cervical Cancer..........................................................................................................................92 

Endometrial Cancer ...................................................................................................................97 

Ovarian Cancer ........................................................................................................................102 
 Priorities of the Gynecologic Cancers 

Progress Review Group
Priorities of the Gynecologic Cancers Progress Review Group 

INTRODUCTION 

BACKGROUND 

Cervical, endometrial, and ovarian cancers 

represent 95 percent of gynecologic cancers 

and collectively rank fourth in both 

incidence and mortality among cancers that 

affect women. It is estimated that 80,300 

women in the United States will be 

diagnosed with a gynecologic cancer 

(cancers of the cervix uteri, corpus uteri, and 

ovary) in 2001 and an estimated 26,300 will 

die of these diseases. Thus, gynecologic 

cancers will account for 14 percent of all 

solid tumors in women and 11 percent of 

deaths from them. Worldwide, gynecologic 

cancers account for an even larger share 

of cancer mortality in women. In nonindustrialized countries, cervical cancer 

screening is minimal; consequently, this 

disease is a major cause of cancer deaths, 

second only to breast cancer in incidence 

and mortality. These three cancers have in 

common their origin in the organs of the 

female reproductive system, but they differ 

dramatically in most other ways. 

As with all solid tumors, the key to the 

control of gynecologic cancers lies in 

understanding their biology. If we can 

identify the genes, proteins, and 

environmental agents that drive their 

initiation and progression, we can make 

significant progress in improving outcomes 

for women at risk for these malignancies. 

We understand, and therefore control, 

cervical cancer best. Our recognition of 

precursor lesions in cervical cancer, and our 

use for nearly 50 years of the Pap test to 

detect them, has all but eradicated invasive 

cervical cancer in developed countries of the 

world. Our more recent discovery that 

infection by the human papillomavirus 

(HPV) is a necessary condition for the 

development of most if not all of cervical 

cancer provides an unprecedented 

opportunity. By developing vaccines against 

HPV infection and/or cervical cancer 

development among those exposed to HPV 

infection, there is the potential to control 

cervical cancer throughout the world. 

Although we do not understand endometrial 

cancer well, we do know the precursor lesion 

for the most common type of disease, and can 

usually detect and diagnose it early enough to 

treat it successfully. However, there is an 

aggressive form of endometrial cancer, type 

II, that, like ovarian cancer, is very poorly 

understood. Ovarian cancer, by far the most 

lethal of the gynecologic cancers in developed 

countries, has presented a challenge to 

researchers because it is not symptomatic 

until late in the disease process. Tumors are 

not easily identified using current methods of 

early detection. Research on biomarkers for 

early detection of ovarian cancer has resulted 

in at least one marker (CA-125) for ovarian 

cancer. CA-125 is currently being tested in 

randomized controlled trials along with an 

imaging method, transvaginal sonography, for 

early detection. In addition, recent 

applications of proteomic techniques have 

shown promise in identifying unique markers 

of ovarian cancer. Nevertheless, much work 

remains to be done in both ovarian and type II 

endometrial cancer if they are to be controlled 

within the next few decades. 

PROCESS 

The Gynecologic Cancer Progress Review 

Group (GYN PRG) was charged with 

identifying and prioritizing areas of research 

to advance progress against these cancers. In 

this process, we attempted to maintain a 

global perspective, and our recommendations 

reflect priorities that will benefit women 

throughout the world. 

Priorities of the Gynecologic Cancers Progress Review Group 1 
At a Planning Meeting held in February 

2001, the GYN PRG organized a Roundtable to consider progress and identify needs 

across the continuum of gynecologic cancer 

research. Topics were selected for breakout sessions and experts were nominated 

to participate in the Roundtable. PRG 

members served as co-chairs for the 

breakout sessions. 

The GYN PRG Roundtable of approxi

mately 120 participants met June 18–20, 

2001, in Herndon, Virginia. Participants 

were assigned to 1 of 14 scientifically 

focused breakout groups and asked to 

identify top priorities for gynecologic 

cancer research in these areas over the 

next 5 years. 

Scientific Breakout Groups at the 

GYN PRG Roundtable Meeting 

• Angiogenesis, Metastasis, and Growth Signaling 

• Defining Signatures of Cancer Cells, Genomics, Proteomics, and Informatics 

• Clinical and Molecular Genetics 

• Early Detection, Screening, and Prevention 

• Genes and Environment 

• Health Disparities, Communication, Education, and Quality of Care 

• Health Related Quality of Life and Survivorship 

• Imaging 

• Immunology 

• Laboratory and Clinical Models 

• Radiobiology 

• Treatment, Clinical Trials, Gene Therapy, Staging, and Surgery 

• Treatment and Drug Discovery 

• Tumor Biology, Hormone Receptors, Epithelial-Stromal Interactions, and Early 

Activation 

In support of the priority-setting process, the Following the scientific breakout sessions, 

Roundtable participants were provided with Roundtable members were convened in three 

analysis of NCI’s gynecologic cancer groups to consider the specific gynecologic 

research portfolio and extensive information tumor types—cancer of the cervix, 

about ongoing NCI initiatives and activities endometrium (uterine corpus), and ovary. 

that might address some of the needs of the These groups were asked to identify gaps in 

field. knowledge and barriers to progress, drawing 

2 Report of the Gynecologic Cancers Progress Review Group 
on the reports of the scientific breakout 

groups. Groups were to recommend four to 

six priorities for research in each specific 

disease type, as well as any recommendations relevant to all three disease sites. 

Finally, the groups were asked to define an 

action plan to achieve the research goals. 

The full reports of the 14 scientific breakout 

groups and the 3 groups addressing specific 

gynecologic tumor types are provided in 

Appendix C. 

OVERVIEW OF PRIORITIES 

Following the Roundtable, the PRG 

leadership used the recommendations of the 

scientific breakout groups and tumorspecific groups to identify an Essential 

Priority, the Virtual Shared Specimen 

Resource (VSSR), an initiative considered 

absolutely necessary for advancing the 

detection, classification, and treatment of 

gynecologic cancer. Three High-Impact 

Priorities provide opportunities to expedite 

progress in our knowledge and understanding of gynecologic cancers and thus 

make significant impacts to reduce the 

burden of disease. Thematically, these 

priorities address either broad, cross-cutting 

research areas or focus on a specific 

gynecologic cancers. Finally, six Scientific 

Opportunities to expedite progress in 

translational research of gynecologic cancers 

were identified. 

ESSENTIAL RESEARCH 

PRIORITY 

HIGH-IMPACT 

PRIORITIES 

SCIENTIFIC 

OPPORTUNITIES 

Develop and make available to the 

cancer research community a 

Virtual Shared Specimen 

Resource (VSSR) to support 

gynecologic cancer research. 

There was consensus among 

members of the Roundtable that 

progress in gynecologic cancer 

research requires timely access to 

high quality samples of human 

tissue and body fluids. 

The VSSR will enable the research 

community to exploit emerging 

genomics, proteomics and 

informatics technologies to identify 

gynecologic cancers early in the 

disease process and to discover new 

targets for their prevention and 

treatment. 

(1) Identify precursor lesions, 

markers of risk and early detection, 

molecular disease classifications, 

prognostic indicators, and new 

targets for prevention and treatment. 

(2) Develop effective human 

papillomavirus (HPV) vaccines to 

prevent biotransmission and 

development of neoplasia. 

(3) Conduct research to (a) understand and improve the quality of life 

of gynecologic cancer patients and 

(b) reduce or eliminate disparities 

related to care among patients with 

gynecologic cancers. 

(1) Characterize the hormonal, 

immunologic, and epithelial-stromal 

interactions that result in the 

development of gynecologic cancers. 

(2) Develop imaging techniques to 

evaluate tumor biology, molecular 

signatures, and therapeutic response. 

(3) Develop preclinical models for 

gynecologic cancers. 

(4) Find ways to overcome resistance 

to chemotherapy and radiotherapy. 

(5) Develop individualized, 

optimized radiation therapy 

techniques in conjunction with other 

treatment modalities. 

(6) Encourage increased participation 

in clinical trials in gynecologic 

cancer. 

As in all types of cancer, the promise of treatment decisions. The establishment of a 

exciting new technologies is that we may be Virtual Shared Specimen Resource (VSSR) 

able to classify gynecologic cancers at the would enable the gynecologic cancers 

molecular level so that we can detect them research community to realize the potential of 

early and diagnose them in ways that guide the emerging technologies that require human 

Priorities of the Gynecologic Cancers Progress Review Group 3 
tissue samples. A cooperative effort of this 

kind, facilitated by the NCI, will speed 

progress in the type of research needed to 

control ovarian and endometrial cancer. The 

time is right for such an initiative. The NCI 

has already begun an important effort to 

work with the research community to define 

the Common Data Elements (CDE’s) that 

describe such specimens. Sharing of 

specimens will enable investigators to 

collaborate across disciplines and 

institutions to answer the most important 

research questions. 

The GYN PRG has formulated the priorities 

and opportunities described in this report to 

stimulate multi-disciplinary research that 

will significantly advance progress against 

these diseases. Implementation of these 

priorities can ultimately lead to discoveries 

that will ameliorate the significant impact of 

the gynecologic cancers on the health and 

lives of American women. 

ESSENTIAL RESEARCH PRIORITY 

THE VIRTUAL SHARED SPECIMEN 

RESOURCE 

Priority: Develop and make available to the 

cancer research community a Virtual 

Shared Specimen Resource (VSSR) to 

support gynecologic cancer research. 

To make significant progress, the 

gynecological cancer research community 

needs to exploit emerging genomics, 

proteomics and informatics technologies to 

identify precursor lesions, markers of risk 

and early detection, molecular disease 

classifications, prognostic indicators, and 

new targets for prevention and treatment. 

Despite a wealth of opportunities, progress 

is impeded by the dearth of high-quality, 

fresh-frozen, annotated specimens available 

to the gynecologic research community. In 

part because technologies are developing so 

rapidly, cutting-edge research requires 

specimens that are obtained at critical points 

in the disease process, processed and stored in 

evolving ways, and associated with highquality clinical and follow-up data. 

The VSSR will allow us to perform molecular 

profiling to identify the molecular signatures 

of gynecologic cancers. It will facilitate the 

discovery of markers of gynecologic cancer 

risk, premalignant and malignant disease, and 

new approaches of preventing and treating 

progressive disease. Specifically, it will 

enable us to achieve answers to the following 

questions, which have been elusive in the 

past: 

• How can women at high risk for 

gynecologic cancers be identified? 

• How can ovarian and endometrial cancers 

be detected early? 

• What strategies can be developed to 

prevent gynecologic cancers? 

• What new approaches can be developed to 

better treat gynecologic cancers? 

Various tissue collection initiatives have been 

proposed and many exist, but they are limited 

in their usefulness for one or more of the 

following reasons: 

• Banked specimens were not processed or 

stored appropriately for current scientific 

needs. 

• Banked specimens were not obtained at 

the appropriate time in the course of 

disease, or do not represent the needed 

tissue types. 

• Informed consent obtained from tissue 

donors was not adequate for current 

scientific needs. 

4 Report of the Gynecologic Cancers Progress Review Group 
• Specimens were not linked to adequate 

clinical data, including demographics, 

risk factors, therapy, and follow-up. 

• Lack of incentives to share specimens 

inhibits widespread use. 

As a result, specimens are not currently 

available in a timely fashion to a large group 

of researchers addressing the critical 

scientific questions in gynecologic cancer 

research. 

Nearly every GYN PRG breakout group 

cited the critical need for quality samples of 

tissue and body fluids for research in 

gynecologic cancer. The groups also pointed 

out that these specimens must be collected 

in a manner to allow adequate preservation 

of DNA and RNA for research use. They 

further listed the need for these specimens to 

be linked to adequate patient data, including 

demographics, risk factors, therapy, and 

follow-up. Where possible, these specimens 

should be serially collected: before 

treatment, during treatment, and at any 

recurrence. Specimens from women without 

gynecologic cancer are needed as well, 

including women with benign gynecologic 

conditions and women with no evidence of 

gynecologic or malignant disease. Finally, 

these specimens and their associated clinical 

data must be collected with appropriate 

informed consent to allow for their use in all 

future research, including techniques yet to 

be developed and questions yet to be asked. 

The VSSR will enable the gynecologic 

cancer research community to realize the 

promise of exciting new technologies to 

identify gynecologic cancers early in the 

disease process and to discover new targets 

for their prevention and treatment. To make 

significant progress, a cooperative effort is 

needed to ensure that the best scientists have 

access to the right specimens. Although the 

scientific community has made efforts to 

this end, it is very difficult. NCI has an 

opportunity to facilitate the scientific 

community efforts and in fact, have already 

begun the process through the definition of 

common data elements to describe the 

specimens. 

Features of the VSSR would include specific 

scientific goals, a coordinating center, and an 

advisory committee to ensure efficiency, 

equity, quality, and inventory control in 

specimen collection, management, and 

distribution. The VSSR is “virtual” in the 

sense that although information describing the 

specimens is managed centrally, the 

specimens themselves reside in various 

institutions. 

The VSSR will surmount existing barriers to 

effective specimen banking and distribution in 

the following ways: 

• Its virtual design will overcome the 

reluctance of institutions that collect 

specimens to have their specimens stored 

centrally. 

• Its central coordination will provide 

equitable access to banked specimens as 

well as providing a means of prospective 

collection of specimens when banked 

specimens are inadequate. 

• Its scientific oversight will ensure that 

appropriate policies are developed 

regarding consortia members’ rights and 

responsibilities, with attention to 

structuring incentives to promote 

collaboration. 

Recommended Actions 

• The National Cancer Institute (NCI) 

should provide the resources needed to 

facilitate development of a VSSR for 

gynecologic cancer research. 

• An advisory committee composed of 

leaders, including advocates, in 

Priorities of the Gynecologic Cancers Progress Review Group 5 
gynecologic cancer research, such as 

members of the GYN PRG, should 

monitor and oversee the progress of the 

resource and the research it supports. 

• Multiple institutions should collaborate 

in the development and use of the VSSR, 

with a long-term goal of serving the 

specimen needs of the larger gynecologic cancer research community. 

Resources 

The VSSR would probably involve multiinstitutional consortia addressing one or 

more of the critical scientific questions 

identified by the GYN PRG, including 

identification of precursor lesions; 

biomarkers of risk, early-stage disease, and 

prognosis; molecular signatures of 

malignant and premalignant lesions; and 

targets for prevention and therapy. Each 

consortium would develop a specimen 

repository to support its own research needs 

as well as those of the larger gynecologic 

research community. 

Fresh tissue and fluids would be obtained at 

critical points in the disease process from 

large numbers of women (hundreds to 

thousands, depending on the research focus), 

including those with and without gynecologic cancer. Rates of specimen accrual for 

rare types of gynecologic cancer (such as 

type II endometrial, stage I serous ovarian, 

and invasive cervical cancers) and other 

conditions of interest (such as prophylactic 

oophorectomy and precursor lesions) would 

be important in selecting consortia. 

Also important would be quality control of 

collection, processing, storage, and 

characterization, as well as the ability to 

collect data on risk factors, clinical aspects, 

follow-up, and outcome by using common 

data elements (CDEs) agreed upon by the 

major NCI networks (Cancer Therapy 

Evaluation Program, Specialized Programs 

Of Research Excellence [SPOREs], Early 

Detection Research Network, etc.). Plans for 

specimen collection and processing would be 

based on the specific research questions to be 

addressed, as well as on the development of a 

more generally useful repository. Expertise in 

genomics, proteomics, and/or informatics 

would be needed within each consortium to 

support specific research goals. Consortia 

would provide access to banked specimens in 

the virtual repository and would initiate 

prospective specimen collection to meet the 

specific goals of new studies for which 

banked specimens were unavailable or 

inadequate. 

The VSSR coordinating center would: 

• Facilitate specimen access by the greater 

research community 

• Manage specimen inventory and data 

• Develop policies and systems to provide 

equitable access to the resource, as well as 

a plan for managing specimen inventory, 

including rapid prospective collection of 

tissue to meet research needs for which 

banked specimens are inadequate 

• Coordinate the work of the collection sites 

across consortia so that the “spigot” can 

be turned on as needed to collect 

specimens of a particular type, to be 

appropriately processed and characterized 

to maintain inventory and/or to meet 

specific scientific objectives 

• Monitor and control the inventory of 

banked specimens to ensure the adequate 

availability of banked specimens to meet 

the needs of the research community 

• Oversee a Specimen Allocation 

Committee, composed of investigators at 

the collection sites, which would approve 

applications for prospective collection of 

unique specimens to meet particular 

6 Report of the Gynecologic Cancers Progress Review Group 
scientific research objectives, as well as 

the use of stored specimens 

• Ensure the appropriate involvement of 

patient advocate groups as resources 

• Provide data collection forms and a 

specimen inventory control and tracking 

system (such as the Biological Specimen 

Inventory), to ensure the use of CDEs, 

facilitate specimen and data sharing, and 

avoid unnecessary investment in 

computer systems at each institution and 

consortium site 

• Provide a website (clearinghouse) to 

support communication with the greater 

research community regarding the ability 

of collection sites to accrue numbers of 

specimens of different types within a 

year, and availability of specimens 

banked already in the repository 

While the GYN PRG hopes that all or 

many of the priorities in this report will 

be addressed, we also believe that there 

can be little progress in gynecologic cancer 

research unless this essential priority is 

implemented. The absence of a dedicated 

specimen resource will preclude timely 

scientific progress in gynecologic cancer 

research. Human specimen resources are 

required to meet the critical scientific 

needs identified in the 2002 NCI Plans 

and Priorities for Cancer Research 

(http://www.planning.cancer.gov), as 

well as those identified in this report. If 

successful, the VSSR could become a 

model for a resource that covers tumor types 

beyond gynecologic cancers. 

HIGH-IMPACT RESEARCH 

PRIORITIES 

Drawing on the discussions of Roundtable 

participants, the PRG leadership identified 

three areas of research: 

• Identification of markers of risk, early 

detection, and targets for treatment 

• Development of human papillomavirus 

vaccines 

• Research to improve patients’ quality of 

life and to reduce disparities related to 

care 

These areas were selected because of their 

importance to the science of gynecologic 

oncology in terms of both the state of the 

science today and the potential for benefit 

over the next 5 years. Two of these priorities 

are relevant to all three gynecologic tumor 

types and encompass areas of the science of 

oncology that also apply to other types of 

cancer. The other priority (HPV vaccines) is 

included as a high-impact priority because it 

has the potential to nearly or completely 

eliminate cervical cancer and thus would have 

a major effect on women’s health throughout 

the world. 

Within each of the three areas, cross-cutting 

priorities for research were culled and 

consolidated from the lists of priorities 

developed by the breakout groups. This 

section presents background information, 

descriptions, and justifications for each of 

these areas. 

MOLECULAR PROFILING FOR MARKERS OF 

RISK, EARLY DETECTION, AND TREATMENT 

Priority: Identify precursor lesions, markers 

of risk and early detection, molecular disease 

classifications, prognostic indicators, and 

new targets for prevention and treatment. 

Cancer control strategies will be most 

effective and economically feasible if 

potentially lethal cancers can be identified 

and treated before they become invasive, 

and if treatment can be appropriately 

targeted. Emerging new technologies offer 

Priorities of the Gynecologic Cancers Progress Review Group 7 
unprecedented opportunities. However, the 

use of these technologies to translate new 

discoveries for patients’ benefits will require 

access to high-quality annotated human 

specimens. 

Although early detection and prevention 

offer the best hope for reducing mortality 

from gynecologic cancers and improving the 

quality of life of cancer survivors, we do not 

have effective screening strategies for 

ovarian cancer or endometrial cancer. 

Identification of cervical intraepithelial 

neoplasia type III (CIN III) as a precursor 

lesion for cervical cancer has allowed us to 

develop effective screening strategies for 

those cancers, but the precursor lesions for 

ovarian cancer and for type II endometrial 

cancer are unknown. 

We also have only limited means of 

identifying women at high risk for 

these diseases. A model of cancer 

risk—such as the Gail model for breast 

cancer enhanced with the addition of 

biomarkers—is needed for the gynecologic 

cancers. To develop risk models and define 

risk groups for ovarian and endometrial 

cancer, we need epidemiologic studies 

conducted in large populations. Such 

models should incorporate markers and 

address long-term risk (i.e., over the 

lifetime) as well as short-term risk (i.e., 

within the next 1 to 5 years). Proteomic 

approaches will make possible the 

development of new markers to identify 

individuals with early-stage cancer or at 

high risk of developing cancer. 

To identify in situ and precursor lesions, a 

two-pronged approach will be needed. In 

addition to research on basic tumor biology, 

including novel ways to understand benign 

but abnormal biology in the pelvis and 

its progression to malignancy, new 

technologies such as genomics and 

proteomics should be used to identify 

precursor lesions and provide their 

molecular signatures. Well-designed 

molecular profiling studies are needed to 

identify the precursor lesions and discover 

their markers. 

Once cancer has been diagnosed, treatment 

recommendations are made on the basis of 

histology and extent of disease, as they have 

been for the past 50 years, yet response to 

treatment varies widely among women with 

the same histologic and clinical features. 

Many women now run the risk of overtreatment with adjuvant therapy, which can 

potentially incur unnecessary expense and 

morbidity. The availability of new 

techniques to identify molecular and genetic 

characteristics of tumors should be combined 

with clinical follow-up data so that molecular 

markers of risk can be incorporated into the 

staging system for gynecologic cancers. 

Molecular and proteomic signatures are 

needed to supplement or replace the role of 

histology and extent of disease in treatment 

decisions, to provide accurate prognostic 

markers, and targets for new therapeutic and 

preventive agents. Partnerships with industry 

will facilitate the development of new 

chemical and biologic therapies directed 

toward the targets identified by molecular 

profiling investigations. 

To advance knowledge in all these areas— 

screening, risk, treatment, and prognosis—we 

must identify molecular markers associated 

with cervical, endometrial, and ovarian 

cancers. Markers for early detection and risk 

will help diagnose cancer in its earliest stages, 

increasing the chances for successful treatment with minimal effects on quality of life. 

Molecular targets for treatment can lead to 

more individualized and less toxic therapies. 

Markers for response to therapy and 

prognosis will also help tailor therapies 

according to the molecular profile of each 

woman’s cancer. 

Achieving this priority would allow us to 

begin to answer the following questions: 

8 Report of the Gynecologic Cancers Progress Review Group 
• What are the precursor lesions associated with epithelial ovarian cancer and 

high-risk endometrial cancer? 

• What biomarkers, measurable in easily 

accessible fluids, are associated with 

these precursor lesions? 

• What biomarkers, measurable in easily 

accessible fluids, are associated with 

invasive gynecologic cancers, especially 

ovarian and high-risk endometrial 

cancer? 

• What biomarkers, measurable in easily 

accessible fluids, are associated with 

response or non-response to therapy? 

• What models of risk, incorporating 

biomarkers as well as family history, 

environmental exposures, and reproductive history, can predict future 

development of epithelial ovarian 

cancer and endometrial cancer? 

• What new approaches can be identified 

for prevention of the gynecologic 

cancers? 

• What is a clinically relevant molecular 

classification and staging system for 

invasive gynecologic cancers? 

• What new targets can be identified for 

which directed therapies can be 

developed to improve survival from the 

gynecologic cancers? 

Recommended Actions 

The NCI is already sponsoring a variety of 

initiatives and projects relevant to the 

molecular profiling of cancers, including the 

Director’s Challenge, the Cancer Genome 

Anatomy Project, and various investigatorinitiated grants. The SPOREs now include 

ovarian cancer and will be expanded to 

include endometrial and cervical cancers. 

However, it will not be possible to make 

progress in comparative genomics and 

proteomics, or in molecular profiling of the 

gynecologic cancers, without an efficient and 

equitable means of ensuring the availability of 

appropriate human specimens. Specimens 

must be accompanied by associated clinical 

information, including medical and family 

history, risk factors, therapeutic interventions, 

response to intervention, and long-term 

follow-up. 

Resources 

The PRG recommends that NCI sponsor a 

mechanism to ensure the availability of three 

types of resources: 

1. Expansion of existing efforts in tumor 

banking is needed to ensure collection of a 

variety of specimens from primary 

surgery, including appropriately processed 

tissue from malignant and benign tumors; 

normal tissue; and urine, blood products, 

and other body fluids obtained at the time 

of diagnosis and serially throughout the 

disease process. Of particular importance 

is the collection of samples from patients 

with potential precursor lesions, earlystage cancers, and no gynecologic cancer. 

Samples of tissue and body fluids must be 

accompanied by associated clinical 

information, including medical and family 

history, epidemiological risk factors, 

therapeutic interventions, and long-term 

follow-up. This resource—which we have 

referred to as the VSSR—is an essential 

research priority. 

2. Large, well-documented specimen 

repositories are needed to allow for the 

development and validation of early 

detection and risk models that incorporate 

markers measured in fluids. Of particular 

interest are repositories that include serial 

specimens from women without cancer at 

entry and with good follow-up data for 

cancer endpoints, such as the Prostate, 

Priorities of the Gynecologic Cancers Progress Review Group 9 
Lung, Colorectal, and Ovarian Cancer 

Screening (PLCO) Trial resource. 

Criteria for access to very valuable 

specimens, such as these, need to be 

developed. 

3. The large randomized controlled trials 

that will eventually be needed to test 

the efficacy of new strategies for 

gynecologic cancer detection and 

prevention are so expensive that we 

can afford to perform a limited number. 

A statistical and bioinformatics 

infrastructure must be developed to 

allow for adequate analysis and 

interpretation of the findings from 

molecular and validation studies to 

ensure that the best strategies are 

selected for testing in trials. 

HUMAN PAPILLOMAVIRUS VACCINES 

Priority: Develop effective human 

papillomavirus (HPV) vaccines to prevent 

biotransmission and development of 

neoplasia. 

Cervical cancer remains one of the leading 

causes of cancer deaths among women 

throughout the world; according to the 

World Health Organization, more than 

230,000 women around the world die each 

year from the disease. Research has made 

clear the primary role of HPV in the 

development of cervical neoplasia; the 

development and implementation of 

effective HPV prophylactic and therapeutic 

vaccines has the potential to nearly eradicate 

cervical cancer. In addition, each year in the 

United States, more than 1,250,000 women 

are diagnosed with potentially precancerous 

changes on Pap smear. The cost to evaluate 

and treat women with abnormal Pap smears 

has been estimated at $6 billion annually. 

Development of effective prophylactic and 

therapeutic vaccines could dramatically 

reduce the cost of screening for cervical 

cancer. 

Although HPV vaccine research has been 

under way for some time, no effective 

prophylactic or therapeutic HPV vaccine has 

been identified. Key issues to be addressed 

include: 

• Role of mucosal and humoral immunity in 

HPV infection 

• Impact of endogenous and exogenous 

factors on the risk of developing cervical 

neoplasia 

• Most efficacious vaccine strategies 

• Immunologic biomarkers that might be 

used to clinically evaluate resulting 

vaccines 

Investigators at the NCI, universities, and 

industry have begun work to develop both 

prophylactic and therapeutic HPV vaccines. 

To date, however, progress has been limited. 

A variety of vaccine strategies have been 

proposed, targeting virus-like particles, 

protein, naked DNA, and bacteria. We lack a 

framework, however, for comprehensive 

clinical evaluation of vaccine combinations, 

adjuvants, and cytokines. Many vaccine 

products are still in preclinical development 

and only a handful has reached clinical 

evaluation. Clinical trials have also been 

hampered by fragmentation of efforts, and 

few partnerships exist between industry and 

government. At present, no effective HPV 

vaccine has been identified for any clinical 

setting, and none has been approved for use 

anywhere in the world. 

Achieving this priority would allow us to 

begin to answer the following questions, 

among others: 

• What are the roles of endogenous (e.g., 

hormones) and exogenous (e.g., other 

pathogens and smoking) factors in 

immunity? 

10 Report of the Gynecologic Cancers Progress Review Group 
• What are the differences between 

immune responses at the systemic level 

and at the mucosal surface or the site of 

neoplasia? 

• How does immune response differ 

between a virus-infected cell and a 

cancer cell? 

• What are the differences between HPVspecific immunity and cervical cancer– 

specific immunity? 

• What are the immunologic profiles at the 

cellular and molecular levels in women 

who develop chronic HPV infection and 

those in whom it is eradicated? 

• Is HPV a sufficient target or are other 

tumor antigens involved in malignant 

transformation? 

• What are the laboratory and biologic 

correlates for vaccine response? 

Recommended Actions 

Although activity has begun for the development of vaccines both for prevention and for 

therapy, gaps in knowledge remain. A 

‘world-wide’ broad-based effort should be 

undertaken to create a network of scientists 

from NCI, industry, the Clinical Trials 

Cooperative Groups, NCI-designated Cancer 

Centers, and individual institutions to 

address existing gaps. Research toward an 

HPV vaccine would be enhanced by: 

1. Encouraging studies to improve our 

basic understanding of mucosal 

immunity in the cervix. 

• Prioritize the understanding of both 

endogenous factors (e.g., influences 

of hormones) and exogenous factors 

(e.g., smoking and other pathogens) 

and their role in influencing mucosal 

immune responses. 

• Define the differences between 

systemic immunity and the immune 

responses at the mucosal surface or 

site of neoplasia. 

2. Understanding the initiation of effective 

mucosal immunity. 

• Define effective anti-viral (HPV) and 

anti-tumor immune responses. 

• Validate laboratory and biologic 

correlates for clinical response. 

• Determine a vaccine strategy that will 

differentiate between the immune 

response to a virally infected cell and 

to a cancer cell. 

• Understand the differences between 

HPV-specific immunity and cervical 

cancer-specific immunity including 

the antigenic repertoire as well as the 

phenotype of both T cell and humoral 

immunity generated at the site of 

disease. 

3. Researching who develops chronic HPV 

infection and in whom it can be 

eradicated. 

• Obtain immunologic profiles of 

women with cervical cancer. 

• Evaluate profiles at both the cellular 

and molecular levels. 

• Include population and epidemiologic 

evaluation in studies to link immune 

defects with other potential environmental concerns. 

• Stimulate biologically relevant antiviral and/or anti-tumor immunity, 

including whether HPV is a sufficient 

target or whether other tumor antigens 

involved in malignant transformation 

are needed for tumor eradication. 

Priorities of the Gynecologic Cancers Progress Review Group 11 
• Define the immunologic problems in 

the development of prophylactic 

versus therapeutic vaccines. 

Resources 

To facilitate the research efforts needed to 

develop effective prophylactic and 

therapeutic vaccines, enhancement of 

existing resources and development of new 

ones in the following areas are critical: 

• Core laboratories for viral and 

immunologic evaluation of specimens 

from clinical trials. 

• A “world-wide” network of clinical 

centers to conduct HPV vaccine studies 

in individuals at risk for HPV infection, 

those infected with HPV, and those with 

cervical neoplasia. 

• An expanded cadre of individuals with 

expertise in clinical trials and HPV 

immunology to conduct future studies. 

• Effective partnerships between industry 

and government to facilitate rapid 

evaluation of new vaccines and vaccine 

combinations and strategies, including 

cytokines and adjuvants. 

• The integration of research efforts world 

wide to ensure that promising new 

efforts receive rapid evaluation and that 

the interventions developed are 

acceptable to women around the world. 

QUALITY OF LIFE: DISPARITIES 

RELATED TO CARE 

Priority: Conduct research to (1) understand and improve quality of life, and 

(2) reduce or eliminate disparities related 

to care among patients with gynecologic 

cancers. 

Much is unknown about how to ensure that all 

women with gynecologic cancers experience 

optimal health-related quality of life. 

Disparities in the care of some patients may 

lead to vastly different outcomes. Significant 

research support is needed to understand and 

to develop interventions that will improve 

quality of life for all women; and to understand and overcome the underlying factors 

that result in disparities in care. 

Understand and improve quality of life. Little 

is known about how to ensure high quality of 

life of gynecologic cancer patients before, 

during and after treatment. Women diagnosed 

with gynecologic cancers often experience 

fatigue, decreased cognitive function, skin 

and hair changes, sexual dysfunction, 

psychosocial problems, and other problems 

that can persist for months to years after 

primary treatment. 

Women in the United States are not routinely 

screened for these symptoms at diagnosis 

or follow-up. There are no effective interventions for many of these symptoms, and 

other aspects of these women’s lives have 

not been well studied: for example, we do 

not know the effect of chemotherapy on 

fertility or the risks of hormone replacement 

therapy after treatment for a gynecologic 

cancer. 

With nearly 20 percent of cancer survivors 

comprised of women who have had cervical, 

endometrial or ovarian cancer, our understanding of their short- and long-term qualityof-life issues—and discovering ways to 

address them—is crucial to providing the 

complete scope of cancer care. Despite the 

scope of the problem, this area remains understudied and under-supported. Additional 

research is badly needed to address questions 

of quality of life and to devise interventions 

for cancer-related and treatment-related 

symptoms. 

12 Report of the Gynecologic Cancers Progress Review Group 
Reduce or eliminate disparities in care. 

Medical science has given us the means to 

effectively treat the majority of gynecologic 

cancers; currently, we cure approximately 

72 percent of cervical cancers, 50 percent of 

ovarian cancers, and 86 percent of cancers 

of the uterine corpus. Nevertheless, studies 

suggest that many U.S. women with 

gynecologic cancer—particularly those with 

ovarian or cervical cancer—do not receive 

optimal care, and that outcomes of care may 

vary widely across populations. 

For example, there are striking disparities in 

stage at diagnosis and in mortality by race 

and socioeconomic status. Black, Asian, 

American Indian, and Hispanic women have 

higher mortality rates from cervical cancer 

than do white women (black women’s rates 

are the highest by far—more than double 

those of white women). Black women also 

have much higher mortality rates from 

endometrial cancer than do whites. In 

ovarian cancer, white women have the 

highest mortality rates, followed by blacks 

and then Hispanics. 

Barriers to receiving optimal screening and 

treatment—whether age-related, educational, cultural, geographic, social, or some 

other type—may explain some of the 

disparities, but research has not elucidated 

which barriers are most important or how to 

overcome them. Many women diagnosed 

with gynecologic cancer are not referred to 

doctors with expertise in the management of 

gynecologic cancer. Specialists who treat 

gynecologic cancers may make assumptions 

based on race, education, or socioeconomic 

status about a woman’s ability to tolerate or 

comply with more aggressive treatment, and 

these assumptions may lead to differences in 

type of treatment offered and, ultimately, 

differences in outcome. 

Screening disparities also exist; older 

women and women in certain areas of the 

United States are less likely to be screened, or 

screened regularly, for cervical cancer. This 

frequently translates into later disease stage at 

diagnosis and worse outcome, even if the best 

care is provided. We need focused research 

to determine how to ensure that all women 

diagnosed with gynecologic cancer in the 

United States receive optimal care. Such 

research must include collaborations among 

investigators with expertise in gynecologic 

oncology, epidemiology, health services 

research, health communication, and health 

psychology. 

Achieving this priority will help answer the 

following questions, among others: 

• What are the short- and long-term 

outcomes among women with 

gynecologic cancers? 

• Are there differences in population 

outcomes related to disparities in 

detection and diagnosis? If so, what can 

be done to eliminate the disparities? 

• What interventions can maintain and 

enhance health-related quality of life 

among women with gynecologic cancers? 

Recommended Actions 

1. We propose large observational cohort 

studies of patients with newly and 

previously diagnosed gynecologic cancer. 

These studies should do the following: 

• Investigate the impact of targeted 

interventions on patient-centered 

outcomes 

• Identify the influence of modifiable 

risk factors on gynecologic cancers 

• Discover options to eliminate 

disparities in the delivery of highquality cancer care 

Priorities of the Gynecologic Cancers Progress Review Group 13 
We recommend that these studies be 

conducted through the newly created, NCIsponsored Cancer Care Outcomes Research 

and Surveillance Consortium (CanCORS) 

initiative. However, it is essential that the 

studies look across the disease continuum, 

from diagnosis through treatment to 

survivorship and end-of-life care, and 

include sites with sufficient representation 

of disadvantaged populations to enable 

examination of health disparities in 

treatment and outcomes. 

2. We propose intensive research to 

develop and evaluate interventions to 

maintain and enhance health-related 

quality of life in women with gynecologic cancers. These efforts would build 

on the ongoing health-related quality of 

life observational research currently 

conducted by the Clinical Trials 

Cooperative Groups, Cancer Centers, 

and individual investigators. It is critical 

that state-of-the-science therapies are 

translated into practice. 

Resources 

To conduct the large observational studies 

required to evaluate quality of care and survivorship issues in gynecologic cancers, new 

research mechanisms will be needed. These 

mechanisms should include the following: 

• Development of collaborative projects 

and consortia to conduct large cohort 

studies in patients with gynecologic 

cancer 

• Collaboration among investigators with 

expertise in gynecologic oncology, 

epidemiology, health services research, 

heath communication, and health 

psychology 

• Development of a cadre of new and 

existing investigators in the fields of 

communication, health psychology, healthrelated quality of life, and health services 

research related to gynecologic cancers 

SCIENTIFIC OPPORTUNITIES 

In addition to identifying high-impact 

priorities, we have identified six Scientific 

Opportunities that should also be an important 

part of the National Cancer Institute’s 

research plan for gynecologic cancer. The 

individual breakout reports (see Appendix C) 

that cited the need for each priority are given 

in parentheses. 

1. Characterize the hormonal, immunologic, and epithelial-stromal interactions that result in the development 

of gynecologic cancers. (Breakouts: 

Tumor Biology, Ovarian Cancer) 

The endometrium, ovary, and cervix are 

all hormone-responsive sites. We do not 

fully understand the etiologic events that 

transform normal epithelial cells into 

hormone-dependent tumors, nor can we 

identify the molecular events in hormoneindependent tumors arising in the 

reproductive tract. We do not understand 

the molecular mechanisms that facilitate 

the interactions and synergy between 

hormones and growth factors and their 

corresponding receptors in both the 

epithelium and the stroma. We do not 

know how aging, race/ethnicity, body 

mass index, puberty, pregnancy, 

menopause, oral contraceptives, hormone 

replacement therapy, or selective estrogen 

receptor modulators influence these 

interactions. 

2. Develop imaging techniques to evaluate 

tumor biology, molecular signatures, 

and therapeutic response. (Breakouts: 

Imaging, Endometrial Cancer, Cervical 

Cancer) 

14 Report of the Gynecologic Cancers Progress Review Group 
Because we can directly visualize the 

transformation zone of the cervix, where 

most neoplasia begins, we have made 

major strides in screening for cervical 

cancer and in deepening our understanding of the biology of preinvasive 

cervical lesions. At present, however, we 

are not able to obtain reliable images of 

precancerous lesions in the endometrium 

or ovary. Although ultrasound and 

magnetic resonance imaging can provide 

information on abnormal structures in 

the adnexa and uterus, no currently 

available imaging modality provides 

effective screening for ovarian 

endometrial cancer or effective biologic 

characterization of cervical, ovarian, or 

endometrial cancer. 

3. Develop relevant preclinical models 

for gynecologic cancers. (Breakouts: 

Genes and Environment, Models, 

Treatment, Endometrial Cancer) 

Gynecologic cancers are characterized 

by unique genetic, physiologic, and 

environmental processes that lead to 

carcinogenesis. Within each gynecologic 

cancer are multiple, heterogeneous 

histologic subtypes. Each gynecologic 

cancer also has a range of biologic 

behaviors, including different patterns of 

growth and metastasis and different 

responses to therapy. Although a variety 

of gynecologic cancer models are in 

development, no models as yet 

recapitulate the human cancer for which 

they were designed. 

4. Find ways to overcome resistance to 

chemotherapy and radiotherapy. 

(Breakouts: Radiobiology, Treatment, 

Cervical Cancer) 

In general, gynecologic cancers are 

initially sensitive to chemotherapy and 

radiation therapy. Nonetheless, in most 

cases, resistant clones develop, resulting 

in death. For example, more than 80 

percent of women with advanced ovarian 

cancer experience a complete clinical 

response to platinum-taxane–based 

chemotherapy after initial surgery, but 

only 25 percent of women with stage 

III/IV ovarian cancer are alive at 5 years. 

More than 80 percent of women with 

locally advanced cervical cancer 

experience a complete clinical response to 

platinum-based chemoradiation, but only 

30 percent of women with stage III/IV 

cervical cancer are alive at 5 years. 

Identification of the mechanisms by which 

gynecologic cancers develop resistance 

would help us improve current treatment 

and cure more women with gynecologic 

cancer. 

5. Develop individualized and optimized 

radiation therapy techniques in 

conjunction with other treatment 

modalities. (Breakouts: Radiobiology, 

Endometrial Cancer, Ovarian Cancer) 

Radiation therapy remains a mainstay of 

treatment for cervical and endometrial 

cancers. Several studies suggest that 

radiation therapy also has great potential 

in the treatment of ovarian cancer. Much 

of the progress to date has been empirical, 

based on patterns of recurrence and 

toxicity. To make further progress, we 

must gain a better understanding of the 

interaction between therapeutic radiation 

and gynecologic cancer, and how 

radiation therapy can be optimized in its 

combination with other treatment 

modalities, such as chemotherapy. 

6. Encourage increased participation in 

clinical trials in gynecologic cancer. 

(Breakouts: Treatment and Drug 

Discovery, Ovarian Cancer) 

Despite the establishment of a subspecialty that is devoted to gyneco

logic cancer, as well as effective 

Priorities of the Gynecologic Cancers Progress Review Group 15 
multidisciplinary collaboration in 

clinical cancer research, less than 2.5 

percent of women with gynecologic 

cancers are enrolled in prospective 

treatment trials. This figure is in marked 

contrast to the 50 percent of children 

with cancer who are entered in clinical 

trials. A variety of new approaches, 

including chemotherapy, biologic 

therapy, immunologic therapy, radiation 

therapy, and hormonal therapy, need 

evaluation in women with gynecologic 

cancer. Progress depends on effective 

communication to women and health 

care providers about the importance of 

clinical trials, and an effective clinical 

trials network with adequate funding for 

translational research. 

CONCLUSION 

The report of the GYN PRG identifies one 

Essential Priority, three High-impact 

Priorities, and six Scientific Opportunities. 

We consider the implementation of these 10 

priorities to be essential if in the next 5 years 

we are to show significant progress toward 

the cure of gynecologic cancer. We 

encourage the reader to study in detail the 

individual reports of the 14 breakout groups 

and the 3 tumor-type groups, which are 

provided in Appendix C. These individual 

reports expand further on the 10 priorities and 

offer additional direction for the research 

community. The material in these reports 

represents the careful considerations of all 

participants at the Roundtable. 

16 Report of the Gynecologic Cancers Progress Review Group 
Appendix A 

About the National Cancer Institute’s 

Progress Review Groups 
Appendix A: About the National Cancer Institute=s 

Progress Review Groups 

The National Cancer Institute (NCI) sup- The following section details the process 

ports basic, clinical, and population-based used to execute these charges. 

research to elucidate the biology, etiology, 

early detection, prevention, and treatment of THE PRG PROCESS 

cancers of various organ sites. These research efforts have produced a substantial PRG members are selected from among 

base of knowledge that, while providing a prominent members of the scientific, mediwealth of new scientific opportunities that cal, and advocacy communities and from 

can further advance our knowledge and pro- industry to represent the full spectrum of 

gress against these diseases, also requires scientific expertise required to make comthat the Institute determine the best uses for prehensive recommendations for the NCI=s 

its resources. cancer research agenda. The membership is 

also selected for its ability to take a broad 

To help ensure the wise use of resources, view in identifying and prioritizing scienNCI has established Progress Review tific needs and opportunities that are critical 

Groups (PRGs) to assist in assessing the to advancing the field of cancer research. 

state of knowledge, reviewing the Institute=s 

research portfolio, and identifying scientific The leadership of each PRG finalizes an 

priorities and needs for its large, agenda and process for a PRG Planning 

site-specific research programs. Meeting. At the Planning Meeting, participants are identified to take part in a subseCHARGE TO THE PRGs quent Roundtable meeting. Topics are identified for Roundtable breakout sessions to 

Each PRG is charged to: which participants will be assigned and for 

which the PRG members will serve as 

$ Identify and prioritize scientific research co-chairs. 

opportunities and needs to advance 

medical progress against the cancer(s) A PRG Roundtable brings together in an 

under review. open forum approximately 100B180 leading 

members of the relevant cancer research, 

$ Define the scientific resources needed to medical, industry, and advocacy communiaddress these opportunities and needs. ties to formulate key scientific questions and 

priorities for the next 5B10 years of research $ Compare and contrast these priorities on specific cancers. As part of the process,

with the current NCI research portfolio. the NCI provides the PRG Roundtable with 

an analysis of its portfolio of cancer research $ Prepare a written report that describes in the relevant organ site. This analysis is findings and recommendations. intended to enable the Roundtable to com-

$ Discuss a plan of action with NCI lead- pare and contrast identified scientific prioriers to ensure that the priority areas are ties with the research currently being done 

addressed. under the Institute=s auspices. Input from the 

Appendix A: About the National Cancer Institute’s Progress Review Groups 17 
Roundtable is used by the PRG in delineating and prioritizing recommendations for 

research, related scientific questions, and 

resource and infrastructure needs. At its discretion, the PRG may solicit additional input 

from the research and advocacy communities through workshops, ad hoc groups, or 

by other means. The PRG also may consider 

the deliberations of previously convened 

expert groups that have provided relevant 

cancer research information. 

THE PRG REPORT 

After the Roundtable, the PRG=s recommendations are documented in a draft report, 

multiple iterations of which are reviewed by 

the PRG leadership and PRG members. The 

final draft report is then submitted for deliberation and acceptance by the NCI Advisory 

Committee to the Director. After the report 

is accepted, the PRG meets with the NCI 

Director to discuss the Institute=s response to 

the report, which is widely disseminated and 

integrated into the Institute=s planning activities. At this meeting, the PRG and the 

NCI identify the research priorities that ongoing NCI initiatives and projects do not 

address. Then the PRG and NCI discuss a 

plan for implementing the highest research 

priorities of the PRG. This plan becomes a 

blueprint for tracking and hastening progress 

against the relevant cancer. 

PRG reports on breast cancer, prostate 

cancer, colorectal cancer, pancreatic cancer, 

lung cancer, brain tumors, and leukemia, 

lymphoma, and myeloma, in addition to this 

PRG report on gynecologic cancers, are 

available online at http://osp.nci.nih.gov. 

Other PRG reports currently in development 

or planned include reports on kidney and 

bladder cancers and on stomach and esophageal cancers. 

18 Report of the Gynecologic Cancers Progress Review Group 
Appendix B 

Gynecologic Cancers PRG 

Membership Roster 
Gynecologic Cancers PRG 

Membership Roster 

William J. Hoskins, M.D. 

PRG Co-Chair 

Memorial Sloan-Kettering Cancer Center 

Nicole Urban, Sc.D. 

PRG Co-Chair 

Fred Hutchinson Cancer Research Center 

Edward C. Trimble, M.D. 

PRG Executive Director 

National Cancer Institute 

Ruedi Aebersold, Ph.D. 

Institute for Systems Biology

Ronald Alvarez, M.D. 

University of Alabama at Birmingham

Garnet L. Anderson, Ph.D. 

Fred Hutchinson Cancer Research Center 

Michael J. Birrer, M.D., Ph.D. 

National Cancer Institute 

Renzo Canetta, M.D. 

Bristol-Myers Squibb 

Pharmaceutical Research Institute 

David Cella, Ph.D. 

Evanston Northwestern Healthcare 

Mary B. Daly, M.D., Ph.D. 

Fox Chase Cancer Center 

Mary (Nora) Disis, M.D. 

University of Washington 

Michael A. Friedman, M.D. 

Pharmacia Corporation 

David M. Gershenson, M.D. 

M.D. Anderson Cancer Center 

Paul Goodfellow, Ph.D. 

Washington University School of Medicine 

Hedvig Hricak, M.D., Ph.D. 

Memorial Sloan-Kettering Cancer Center 

Loretta Itri, M.D. 

Genta, Inc. 

Beth Y. Karlan, M.D. 

Cedars-Sinai Medical Center 

Douglas R. Lowy, M.D. 

National Cancer Institute 

Samuel Mok, Ph.D. 

Brigham and Women’s Hospital 

Cherie Nichols, M.B.A. 

National Cancer Institute 

Edward Partridge, M.D. 

University of Alabama at Birmingham

Karl Podratz, M.D., Ph.D. 

Mayo Clinic 

Marcus E. Randall, M.D. 

Indiana University School of Medicine 

Martha C. Romans, B.A. 

Jacobs Institute of Women’s Health 

Mary Jackson Scroggins, M.A. 

Ovarian Cancer National Alliance 

Branimir I. Sikic, M.D. 

Stanford University Medical Center 

James Tate Thigpen, M.D. 

University of Mississippi Medical Center 

Jane Weeks, M.D. 

Dana-Farber Cancer Institute 

Stacey Young-McCaughan, R.N., Ph.D. 

Congressionally Directed Medical 

Research Programs 

Richard J. Zaino, M.D. 

Hershey Medical Center 

Appendix B: Gynecologic Cancers PRG Membership Roster 19 
Appendix C 

Gynecologic Cancers PRG 

Roundtable Participants Roster 
Gynecologic Cancers PRG Roundtable 

Participants Roster 

Ruedi Aebersold, Ph.D. 

Institute for Systems Biology 

Ronald Alvarez, M.D. 

University of Alabama at Birmingham

Barbara Andersen, Ph.D. 

Ohio State University 

Garnet L. Anderson, Ph.D. 

Fred Hutchinson Cancer Research Center 

Jeffrey Arbeit, M.D. 

University of California, San Francisco 

Carolyn M. Ballard, C.H.E. 

Virtua Health 

Richard Barakat, M.D. 

Memorial Sloan-Kettering Cancer Center 

Robert Bast, M.D. 

M.D. Anderson Cancer Center 

William T. Beck, Ph.D. 

University of Illinois at Chicago 

Deborah Bell, M.B.A. 

Ovarian Problems Discussion List 

Andrew Berchuck, M.D. 

Duke University Medical Center 

Michael J. Birrer, M.D., Ph.D. 

National Cancer Institute 

Mark Boguski, M.D., Ph.D. 

Rosetta Inpharmatics 

Jeff Boyd, Ph.D. 

Memorial Sloan-Kettering Cancer Center 

Mark Brady, Ph.D. 

Roswell Park Cancer Institute 

Richard Buller, M.D., Ph.D. 

Holden Comprehensive Cancer Center 

John D. Chapman, Ph.D. 

Fox Chase Cancer Center 

Robin Chin, R.Ph. 

National Asian Women’s 

Health Organization 

Kathleen Cho, M.D. 

University of Michigan Medical School 

Louise Chow, Ph.D. 

University of Alabama at Birmingham

Larry Copeland, M.D. 

Ohio State University 

Terri Cornelison, M.D. 

National Cancer Institute 

James Corrigan, Ph.D. 

National Cancer Institute 

Peggy A. Crowley-Nowick, Ph.D. 

Brigham and Women’s Hospital 

Mary B. Daly, M.D., Ph.D. 

Fox Chase Cancer Center 

Farrokh Dehdashti, M.D. 

Washington University School 

of Medicine 

Mary (Nora) Disis, M.D. 

University of Washington 

Appendix C: Gynecologic Cancers PRG Roundtable Participants Roster 21 
Deborah Duran, Ph.D. 

National Cancer Institute 

Lora Hedrick Ellenson, M.D. 

Weill Medical College of Cornell 

University 

Mona Fouad, M.D., M.P.H. 

University of Alabama at Birmingham

Jane Fountain, Ph.D. 

National Cancer Institute 

Ralph S. Freedman, M.D., Ph.D. 

M.D. Anderson Cancer Center 

Michael A. Friedman, M.D. 

Pharmacia Corporation 

Holly Gallion, M.D. 

University of Kentucky 

Judy Garber, M.D. 

Dana-Farber Cancer Institute 

Diana Patricia Garcia, B.S. 

Public Relations 

David M. Gershenson, M.D. 

M.D. Anderson Cancer Center 

Barry B. Goldberg, M.D. 

Thomas Jefferson University Hospital 

Patricia Goldman 

Ovarian Cancer National Alliance 

Paul Goodfellow, Ph.D. 

Washington University School 

of Medicine 

Lester Gorelic, Ph.D. 

National Cancer Institute 

Thomas C. Hamilton, Ph.D. 

Fox Chase Cancer Center 

Silvia Curtis Hewitt, M.A. 

National Institute of Environmental 

Health Sciences 

William Hoskins, M.D. 

Memorial Sloan-Kettering Cancer Center 

Hedvig Hricak, M.D., Ph.D. 

Memorial Sloan-Kettering Cancer Center 

Loretta Itri, M.D. 

Genta, Inc. 

Deborah Jaffe, Ph.D. 

National Cancer Institute 

Diana Jeffery, Ph.D. 

National Cancer Institute 

Beth Y. Karlan, M.D. 

Cedars-Sinai Medical Center 

Ann Kolker, B.A. 

Ovarian Cancer National Alliance 

Robyn Kravit, M.A. 

Tethys Research 

Yi-Shin Kuo, M.D. 

National Asian Women’s 

Health Organization 

Robert Lenkinski, Ph.D. 

Beth Israel Deaconess Medical Center 

Kimberly Leslie, M.D. 

University of Colorado 

Health Sciences Center 

Charles Levenback, M.D. 

M.D. Anderson Cancer Center 

Anna T. Levy, M.S. 

National Cancer Institute 

David N. Louis, M.D. 

Massachusetts General Hospital 

22 Report of the Gynecologic Cancers Progress Review Group 
Susan Lowell-Butler 

Ovarian Cancer Coalition 

of Greater Washington 

Douglas R. Lowy, M.D. 

National Cancer Institute 

Nita Maihle, Ph.D. 

Mayo Clinic 

Cheryl Marks, Ph.D. 

National Cancer Institute 

Trish May, M.B.A. 

Fred Hutchinson Cancer Research 

Center Foundation 

John McPherson, Ph.D. 

Washington University School 

of Medicine 

Marc S. Mendonca, Ph.D. 

Indiana University School of Medicine 

Samuel Mok, Ph.D. 

Brigham and Women’s Hospital 

Franco Muggia, M.D. 

New York University Medical Center 

Carolyn Muller, M.D. 

Southwestern Medical Center 

David Mutch, M.D. 

Washington University School 

of Medicine 

Kate Nagy, M.A. 

National Cancer Institute 

Susan G. Nayfield, M.D. 

National Cancer Institute 

Pat Newman 

National Cancer Institute 

Cherie Nichols, M.B.A. 

National Cancer Institute 

Peter J. O’Dwyer, M.D. 

University of Pennsylvania Cancer Center 

Peggy Olive, Ph.D. 

British Columbia Cancer Research Center 

Kevin G. Osteen, Ph.D. 

Women’s Reproductive Health 

Research Center 

Groesbeck Parham, M.D. 

University of Arkansas for Medical 

Sciences 

Edward Partridge, M.D. 

University of Alabama at Birmingham

Karl Podratz, M.D., Ph.D. 

Mayo Clinic 

Sundaram Ramakrishnan, Ph.D. 

University of Minnesota 

Marcus E. Randall, M.D. 

Indiana University School of Medicine 

Timothy Rebbeck, Ph.D. 

University of Pennsylvania 

Martha C. Romans, B.A. 

Jacobs Institute of Women’s Health 

Neeraja Sathyamoorthy, Ph.D. 

National Cancer Institute 

Susan L. Scherr, A.A. 

National Coalition for 

Cancer Survivorship 

Mark Schiffman, M.D. 

National Cancer Institute 

Joellen Schildkraut, Ph.D. 

Duke University Medical Center 

Mary Jackson Scroggins, M.A. 

Ovarian Cancer National Alliance 

Appendix C: Gynecologic Cancers PRG Roundtable Participants Roster 23 
Rivienne Shedd-Steele, B.A. 

Cancer Information Service 

of the National Cancer Institute 

Ellen Sheets, M.D. 

Brigham and Women’s Hospital 

Branimir I. Sikic, M.D. 

Stanford University Medical Center 

Steven Skates, Ph.D. 

Massachusetts General Hospital Center 

Diane Solomon, M.D. 

National Cancer Institute 

M. Sharon Stack, Ph.D. 

Northwestern University Medical School 

James Tate Thigpen, M.D. 

University of Mississippi Medical Center 

Jeffrey Trent, Ph.D. 

National Human Genome 

Research Institute 

Cornelia Trimble, M.D. 

Johns Hopkins University 

School of Medicine 

Edward C. Trimble, M.D. 

National Cancer Institute 

Nicole Urban, Sc.D. 

Fred Hutchinson Cancer Research Center 

Annabelle Uy, M.S. 

National Cancer Institute 

Barbara Vanderhyden, Ph.D. 

Ottawa Regional Cancer Centre 

Joan Walker, M.D. 

Oklahoma University 

Health Sciences Center 

Jane Weeks, M.D. 

Dana-Farber Cancer Institute 

Michael Welch, Ph.D. 

Washington University 

School of Medicine 

Lari Wenzel, Ph.D. 

University of California, Irvine 

John Wiktorowicz, Ph.D. 

Lynx Therapeutics, Inc. 

Judith Wolf, M.D. 

M.D. Anderson Cancer Center 

Aaron Wolfson, M.D. 

University of Miami 

School of Medicine 

T. C. Wu, M.D., Ph.D. 

Johns Hopkins University 

School of Medicine 

Stacey Young-McCaughan, R.N., Ph.D. 

Congressionally Directed Medical 

Research Programs 

Richard J. Zaino, M.D. 

Hershey Medical Center 

24 Report of the Gynecologic Cancers Progress Review Group 
Appendix D 

Reports of the Gynecologic Cancers PRG 

Roundtable Breakout Groups 
Health-Related Quality of Life and Survivorship 

Co-Chairs: Stacey Young-McCaughan, David Cella, and Barbara Andersen 

Participants: 

Deborah Bell Diana Jeffery Joan Walker 

Robin Chin Edward Partridge Jane Weeks 

Mona Fouad Susan L. Scherr Lari Wenzel 

Diana Patricia Garcia Mary Jackson Scroggins 

BACKGROUND: STATE 

OF THE SCIENCE 

Improved therapies and supportive care 

measures are improving survival rates and 

durations for women with both primary and 

recurrent gynecologic cancers. Accordingly, 

issues concerning health-related quality of 

life and survivorship are becoming a more 

urgent concern. Of the approximately 3.9 

million women alive today with a history of 

any type of cancer, nearly 20 percent 

(656,108) have been diagnosed with a 

gynecologic cancer. Yet only 3 percent of 

the survivorship research funded by the 

National Institutes of Health and the 

Department of Defense (DoD) addresses the 

concerns of women with gynecologic 

cancers. 

The collective research portfolio of the 

National Cancer Institute (NCI), the 

Gynecologic Oncology Group (GOG), the 

DoD, and the American Cancer Society 

contains fewer than 25 studies on healthrelated quality of life and survivorship 

among patients with gynecologic cancer. 

These studies are primarily investigatorinitiated, descriptive studies of women 

with ovarian or cervical cancer or are drug 

intervention studies funded by the GOG 

in which quality of life is added as an outcome measure. Four intervention studies 

examined psychologic interventions, interventions for sexual dysfunction, and an 

exercise intervention. Several of the studies 

dealt with a relatively small proportion of the 

population of women with gynecologic 

cancers, such as those with germ cell tumors 

or BRCA1 mutations. 

Health-related quality of life and survivorship 

studies can be reviewed by at least five NCI 

study sections (Social Sciences, Nursing, 

Epidemiology, and Methods; Nursing 

Research; Biobehavioral and Behavioral 

Processes; Prevention and Health Behavior; 

or a special study section) and can be funded 

by at least three NCI divisions (Cancer 

Treatment and Diagnosis, Cancer Prevention, 

and Cancer Control and Population Sciences). 

Thus, investigators are often confused as to 

potential NCI program officers or where to 

send their proposals for review and funding. 

The DoD does not have any special funding 

mechanisms for health-related quality of life 

or survivorship proposals, instead requiring 

investigators to submit their best ideas under 

more generic award mechanisms. Very few 

proposals having to do with health-related 

quality of life have been submitted or funded 

by the DoD. 

Issues related to health-related quality of life 

and survivorship for the gynecologic cancers 

include the following: 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 25 
All Gynecologic Cancers (cervical, 

endometrial, ovarian) 

• Study is needed to ascertain the role and 

optimal administration of hormone replacement therapy in the care of women 

who are at risk for, as well as those 

diagnosed with, gynecologic cancers. 

• There is a need for longitudinal, 

descriptive studies in most areas of 

research on health-related quality of life 

and survivorship as a basis for 

thoughtfully designed intervention 

studies. In particular, virtually nothing 

is known of the quality of life of women 

who have survived endometrial cancer, 

although it has the highest overall 

survival rate of the gynecologic cancers. 

• Areas needing assessment include symptom experience and intensity, skin and 

hair changes, memory loss, and aging. 

No additional descriptive studies of 

sexual dysfunction are needed, as the 

sexual sequelae to the diagnosis and 

treatment of gynecologic cancers have 

been carefully documented and 

validated. 

• There is a need for a description of the 

effects of secondary and tertiary 

treatments, as well as those of chronic 

treatment for recurrent cancer. 

• There is a need for a description of the 

long-term effects of chemotherapy and 

radiation therapy. 

• Population-based documentation of 

patterns of care is also needed. 

Cervical Cancer 

• Sexuality and reproductive concerns 

• Quality of life, especially as it relates to 

the social stigma and socioeconomic 

status associated with the disease 

• Communication with health professionals 

• Cultural sensitivity to age, race, ethnicity, 

and environment 

• Access to care 

Endometrial Cancer 

• Care of women with comorbid conditions, 

such as obesity and diabetes 

• Sense of well-being and body image 

• Physical functioning 

• Dietary and exercise interventions 

• Connections with other cancers, such as 

colon cancer 

• Well-woman care and health-seeking 

behavior 

Ovarian Cancer 

• Fear of recurrence 

• Treatment decision-making 

• Social support interventions 

• Supportive and palliative care 

• End-of-life care 

• Education and communication 

• Insurance issues 

26 Report of the Gynecologic Cancers Progress Review Group 
RESEARCH PRIORITIES 

Priority 1: Intervention research 

addressing sexuality and fertility outcomes 

in women with gynecologic cancers. 

Rationale 

Longitudinal research has documented that 

as many as 50 percent of patients with 

gynecologic cancer experience significant 

sexual difficulties after diagnosis and 

treatment. Difficulties arise during the 

immediate post-treatment period; if left 

untreated, they do not resolve and may 

worsen with time. When sexual difficulties 

are studied in the context of other major life 

areas (e.g., mood, social adjustment, 

employment), they remain an island of 

disruption in an otherwise generally positive 

survivorship scenario. Thus, with a 

substantial research basis of descriptive 

efforts, it is now appropriate to begin 

intervention research to prevent or remediate 

these difficulties. This effort will be 

facilitated by the availability of efficacious 

treatments for the treatment of female sexual 

dysfunctions. 

Complementary concerns for many young 

cancer patients are the effects of cancer 

therapy on fertility, as well as the 

availability of therapies to treat symptoms of 

menopause. The risk/benefit study of 

hormone replacement therapy in women 

with gynecologic cancers is of particular 

interest. 

Barriers 

Sexuality and fertility issues often are not 

easily discussed, either between partners or 

with health care professionals. This 

reticence makes it difficult to study 

interventions that address sexuality and 

fertility outcomes. 

Resources Needed 

Trained professionals are needed to broach 

sexuality and fertility issues and to design 

appropriate intervention studies. With 

professional encouragement and adequate 

funding for research, investigators will be 

more likely to devote their careers to the 

study of gynecologic cancers. 

Priority 2: Research on quality-of-life issues 

surrounding the late effects of treatment and 

long-term survival. 

Rationale 

Advances in gynecologic care and treatment 

have lengthened disease-free intervals and 

have improved survival rates. Survival 

advances have been achieved through the 

effective use of combination therapies (e.g., 

chemoradiation for cervical cancer), lengthy 

treatment regimens, and the use of multiagent chemotherapy regimens. Thus, most 

gynecologic cancer patients reach 5-year 

survival periods (and longer) and cope with 

the accompanying changes that may have 

occurred in their quality of life. Knowledge is 

needed regarding the scope and magnitude of 

psychosocial difficulties confronting these 

long-term survivors, including predictors, 

magnitude, and course of psychosocial 

responses and outcomes. These issues are 

particularly important for patients receiving 

multiple therapies or therapies with late 

effects, as well as for those who have medical 

comorbidities or limited socioeconomic 

resources at the time of their diagnoses. 

Barriers 

Although gynecologic tumors account for 14 

percent of annual cancer cases in women and 

nearly 20 percent of female cancer survivors, 

minimal attention and study have focused on 

the quality-of-life and survivor concerns of 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 27 
these women. This absence of research, 

though driven in part by lack of funding, is 

also due to the absence of a cadre of trained 

investigators devoting their careers to the 

study of health-related quality-of-life issues 

among patients with and survivors of 

gynecologic cancers. 

Resources Needed 

To better describe quality-of-life issues 

surrounding the late effects of treatment and 

long-term survival, a Cancer Care Outcomes 

Research and Surveillance Consortium 

(CanCORS) award or similar mechanism for 

the gynecologic cancers is needed. This 

mechanism should focus on patient-centered 

outcomes, investigating the dissemination of 

state-of-the-science therapies into community 

practice, examining the influence of modifiable risk factors, and analyzing disparities in 

the delivery of quality cancer care. 

Furthermore, funding mechanisms are needed 

to bring new investigators into the field, 

provide training resources to senior 

investigators for mentorship, and induce 

psychosocial investigators to focus research 

programs on gynecologic tumors. In turn, 

these new investigators and more senior 

investigators can serve as mentors for future 

researchers. 

28 Report of the Gynecologic Cancers Progress Review Group 
Clinical and Molecular Genetics 

Co-Chairs: Mary B. Daly and Judy Garber 

Participants: 

Richard Barakat Holly Gallion 

Andrew Berchuck Beth Y. Karlan 

Jeff Boyd Robyn Kravit 

Richard Buller Samuel Mok 

BACKGROUND: STATE 

OF THE SCIENCE 

Emerging technologies in molecular biology 

and genetics are providing new and 

powerful tools with which to explore 

gynecologic malignancies and describe 

tumor heterogeneity. Despite the 

sophistication of these new technologies, 

their clinical application to the prevention, 

early detection, and treatment of ovarian, 

endometrial, and cervical cancers is lagging. 

Progress in molecular genetics has the 

potential to elucidate the basic mechanisms 

of tumor initiation, growth, and invasion; 

identify molecular targets for prevention, 

screening, and treatment; and explore genegene and gene-environment interactions. A 

systematic approach to exploit this potential 

has not been initiated, however. Clinical 

assays can now identify individuals with 

germline mutations who face a significantly 

increased risk for ovarian or endometrial 

cancer, yet clinicians caring for these 

individuals have very little to offer beyond 

surgical preventive strategies. Furthermore, 

the clinical phenotypes of hereditary cancers 

are not well defined and optimal treatment 

strategies are lacking. Larger societal issues 

of public and professional education and 

ethical concerns in the protection of privacy 

and confidentiality must also be addressed. 

Carolyn Muller 

Susan G. Nayfield 

Timothy Rebbeck 

Joellen Schildkraut 

In this area, attention must be paid to the 

following: 

• Novel and powerful technologies that can 

potentially characterize the molecular 

evolution of gynecologic malignancies 

have recently become widely available. 

These tools permit the identification of 

points of molecular commonality across 

cancers and have tremendous potential for 

translational research. 

• The molecular heterogeneity observed in 

gynecologic tumors may provide 

important clues to the role of genetic and 

environmental exposures and may help 

define gene-gene and gene-environment 

interactions. 

• A concerted effort is needed to translate 

important molecular discoveries into 

clinical applications. However, a 

significant gap in the knowledge and 

appreciation of the promise of genetics 

within the medical community hinders the 

incorporation of these findings into 

clinical care. 

• Complex ethical, cultural, and societal 

barriers to the conduct of genetic research 

must be addressed. These barriers include 

fear of genetic discrimination, concerns 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 29 
about privacy and confidentiality, and 

fragmentation of the regulatory bodies 

that oversee research. 

• Markers of inherited risk for ovarian and 

endometrial cancers are now available in 

the clinical setting and are being utilized 

by clinicians. A better understanding of 

these inherited cancers will provide 

insights into the carcinogenic pathways 

in sporadic as well as inherited cancers. 

There is, however, a profound lack of 

information about strategies for early 

detection, the role of chemoprevention, 

the risks and benefits of prophylactic 

surgeries, and the importance of the 

traditional risk factors in these 

individuals. 

• There is some evidence that inherited 

cancers are different from their sporadic 

counterparts. For example, BRCA1/2-

associated ovarian cancers appear to 

have a better prognosis than do sporadic 

ovarian cancers. The details of any 

biologic differences between hereditary 

and sporadic gynecologic cancers must 

be defined to permit assessment of the 

extent to which hereditary cancers can 

serve as models for early detection, 

prevention, and treatment interventions 

that can be generalized to the larger 

population, as well as to individualize 

treatment options to match the biologic 

characteristics of the tumors. 

RESEARCH PRIORITIES 

Priority 1: New and emerging molecular 

technologies must be applied to gynecologic 

cancers, where the need for effective 

therapies is critical. We must characterize 

the molecular features of gynecologic 

cancers for the identification of intermediate 

biomarkers for prevention, molecular 

targets for early detection and treatment, 

and factors with prognostic and predictive 

significance. 

Priority 2: Populations at risk for inherited 

cancers are an ideal group for pilot studies of 

etiology and prevention. It is critical to study 

genetically high-risk individuals and their 

cancers to identify genetic and environmental 

determinants of penetrance, to compare and 

contrast hereditary and sporadic cancers, to 

address issues of clinical management, and to 

extend this knowledge to the field of 

pharmacogenetics. 

Priority 3: Genetic identification of 

individuals at high risk is possible for all 

three common gynecologic cancers. Modifier 

genes and genetic polymorphisms are also 

being identified that increase susceptibility. 

In other malignancies, there exist effective 

therapeutic interventions directed against 

molecular targets. Research must emphasize 

the translation of genetic and molecular 

paradigms into clinical applications and 

define effective strategies to prepare the 

public and medical communities to embrace 

these revolutionary approaches. New models 

will affect risk assessment, targeted 

surveillance, prevention, and treatment. 

BARRIERS 

Despite progress in federal and state privacy 

legislation, concerns about genetic 

discrimination remain significant for many 

individuals who would otherwise participate 

in informative research. Additional efforts to 

ensure protection from discrimination in 

health insurance, employment, and other 

opportunities on the basis of genetic 

information remain critically important to 

permit ongoing research in the genetics of 

gynecologic malignancies. 

Protection of the rights of research 

participants and their family members to 

privacy and confidentiality is the charge of 

Institutional Review Boards and the Office of 

Human Research Protection. These bodies 

must be educated and supported as they 

devise systems to protect participants without 

30 Report of the Gynecologic Cancers Progress Review Group 
hindering research that depends on access to 

critical human blood and tissue specimens 

and, sometimes, on ongoing contact with 

participants. These systems must balance 

the rights to individual privacy against the 

burden of “overconsenting” and must 

consider the special issues raised by genetic 

studies, which may have implications for 

family members. 

Genetic testing for hereditary susceptibility 

to cancer is limited by financial and 

sociocultural factors. Despite increasing 

coverage of genetic testing by health 

insurance companies, access to genetic tests 

for individuals without health insurance or 

with less comprehensive policies—more 

than 12 million Americans annually—is not 

available. Sociocultural barriers to genetic 

testing are also important to issues of access 

and utilization. These must be addressed 

both practically and as appropriate topics for 

research. 

RESOURCES 

• For the goals described herein, 

meticulously collected and verified 

clinical treatment and outcome data are 

critical. Coordinated access to existing 

resources must also be addressed. 

• A resource of germline and malignant 

tumor material with associated clinical 

data from individuals with hereditary 

predisposition to cancer would greatly 

facilitate the elucidation of the proposed 

research goals. Such collection might be 

facilitated through the Cancer Family 

Registries, the Cancer Genetics Network, 

or other programs. 

• Mechanisms must be developed to 

facilitate funding for and conduct of 

correlative science investigations in 

gynecologic malignancies within the 

cooperative treatment groups from their 

existing and developing characterized 

tissue repositories. 

• Special mechanisms must be developed 

with which to attract young investigators 

to molecular biologic and translational 

research in gynecologic malignancies. 

• Mechanisms to foster collaborative 

research and encourage interaction across 

disciplines must be emphasized. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 31 
Defining Signatures of Cancer Cells, Genomics, Proteomics, 

and Informatics 

Co-Chairs: Ruedi Aebersold, Garnet L. Anderson, and Mark Boguski 

Participants: 

Robert Bast Trish May Jeffrey Trent 

Michael J. Birrer Neeraja Sathyamoorthy Michael Welch 

Kathleen Cho Mark Schiffman John Wiktorowicz 

Nita Maihle Steven Skates 

BACKGROUND: STATE 

OF THE SCIENCE 

The availability of the complete human 

genomic sequence and emerging 

technologies for the systematic and 

quantitative measurement of the genes 

(genomics) and proteins (proteomics) 

expressed by a cell or tissue provide new 

opportunities to define molecular signatures 

of cancer. Such signatures are expected to 

have an impact on essentially any type of 

cancer and on topics of cancer research, 

such as the study of the molecular 

mechanisms of cancer, early detection, 

diagnosis, discovery of new treatment 

targets, and assessment of treatment 

outcome. 

The generation of biologically and clinically 

relevant signatures in gynecologic cancers 

via genomic and proteomic tools critically 

depends on the availability of high-quality, 

well-annotated samples. Furthermore, the 

detection of signatures consisting of 

multiple elements requires the analysis of 

relatively large numbers of samples to make 

the signatures statistically significant. 

Although genomic and proteomic 

technologies are still rapidly evolving, their 

initial application has indicated that the 

development of meaningful molecular 

signatures requires the development of new 

study designs, integrated databases, advanced 

computational tools, and centers for highthroughput data generation. Technology 

centers subject to these recommendations are 

expected to significantly accelerate the access 

of cancer biologists to state-of-the-art 

analytical facilities and to provide an urgently 

needed pool of researchers trained in 

emerging technologies. 

RESEARCH PRIORITIES 

Priority 1: Develop a national resource for 

the collection and distribution of clinical 

samples. 

• The resource will contain high-quality, 

well-annotated specimens including 

normal, benign, and pre-malignant 

lesions; all histologies and stages; and 

specimens from various risk groups. The 

number of specimens will be sufficiently 

high to support studies leading to 

statistically significant conclusions. 

• The specimen resource will ideally 

include matched (tissue and blood) and 

serial samples from the same patient. 

• Specimens will be annotated with clinical, 

pathologic, epidemiologic, and molecular 

signatures specific for each tumor type. 

32 Report of the Gynecologic Cancers Progress Review Group 
Barriers 

Although a number of tissue collection 

initiatives exist, the following factors have 

limited usefulness for defining signatures of 

cancer: 

• Lack of standardized protocols for the 

collection and annotation of high-quality 

specimens 

• Lack of sufficiently large matched 

sample sets to support studies yielding 

statistically significant conclusions 

• Lack of appropriately trained personnel 

• Lack of infrastructure for the 

decentralized collection of specimens 

representing the whole population 

• Lack of standardized criteria to provide 

access to rare specimens 

• Privacy and informed consent policies 

that constrain the use of specimens for 

unanticipated studies 

Resources 

• Existing specimen banks such as the 

Gynecologic Oncology Group, the Early 

Detection Research Network, the Cancer 

Genetics Network, Ovarian Specialized 

Program of Research Excellence, and 

private-sector programs 

• Patient advocate groups as resources for 

raising patient participation in donor 

programs and for addressing 

constraining privacy and informed 

consent policies 

Priority 2: Develop optimal study design 

and data analysis methods. These methods 

will define appropriate sample sizes and 

comparison groups to achieve statistical 

significance and will be informed by 

biologic and experimental variability. 

Barriers 

• Lack of data and high-quality samples to 

assess biologic and experimental variation 

• Lack of a mathematical paradigm for 

interpreting high-dimensional data 

analysis 

Resources 

• Rich source of analytical tools developed 

for other scientific disciplines that are 

adaptable to this setting 

Priority 3: Establish Centers of Excellence to 

apply leading-edge technologies to discover 

and validate signatures of cancer. These 

centers will provide the following: 

• Cost-efficient access to integrated 

technology platforms 

• Training and education in the use of these 

technologies 

• Access to advanced computing resources 

for data management and analysis 

Barriers 

The definition of molecular signatures by the 

systematic analysis of gene expression 

requires integrated facilities consisting of 

trained personnel, instrumentation for data 

generation, and computational infrastructure 

for data management and analysis. The 

following factors limit the ability to generate 

molecular signatures of cancer: 

• Lack of databases and software tools for 

integrating large, diverse, and complex 

data sets 

• Lack of availability of specialized 

advanced computing resources 

• Lack of standardized open-source tools 

for data representation and query 

languages 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 33 
• Lack of trained personnel at all Resources 

levels 

• Targeted programs for development 

• Lack of awareness of the require- of innovative technologies by the 

National Cancer Institute 

ments and the potential of the 

technologies by cancer biologists • Potential for private/public sector 

partnerships 

34 Report of the Gynecologic Cancers Progress Review Group 
Treatment and Drug Discovery 

Co-Chairs: Peter J. O’Dwyer and Branimir I. Sikic 

Participants: 

William T. Beck Barry B. Goldberg Susan Lowell-Butler 

Mark Brady Ann Kolker 

Larry Copeland Yi-Shin Kuo 

David M. Gershenson 

BACKGROUND: STATE 

OF THE SCIENCE 

The three major gynecologic cancers differ 

appreciably in their biologic and clinical 

characteristics and treatment approaches. 

Ovarian cancer is considered moderately 

responsive to many cytotoxic agents, 

particularly platinum drugs and taxanes. 

Although the large majority of patients 

respond favorably to initial therapy, only 20 

to 30 percent of patients with stage III 

disease are cured. Thus, drug resistance is 

still a dominant feature in this disease. 

Cancers of the cervix and endometrium are 

less responsive to cytotoxins than are 

ovarian epithelial cancers. Cancers of the 

cervix are characterized by a human 

papillomavirus etiology, the availability of a 

screening test to detect early stages, and the 

recent demonstration of major clinical 

benefit from combining chemotherapy and 

radiation therapy in localized but bulky 

tumors. Endometrial cancers arise in a 

much older population of women, and their 

etiology involves hormonal mechanisms. 

Considerable current research in the 

pharmaceutical industry has focused on 

developing new or improved cytotoxic 

agents. Examples include analogs of 

platinums and taxanes with improved 

toxicity and antitumor activity profiles, 

Franco Muggia 

Sundaram Ramakrishnan 

and the development of epothilones as noncross-resistant antitubulin drugs. Some of 

these cytotoxins are likely to prove beneficial 

for patients with gynecologic cancers because 

of increased antitumor activity and/or lower 

toxicity than current agents. 

The past year in cancer therapy has been 

noteworthy for the approval of one of the first 

drugs that inhibits tyrosine kinase growth 

signaling. Gleevec, or STI-571, is a splendid 

example of how knowledge about the 

molecular pathogenesis of a cancer can lead 

to the identification of a therapeutic target, 

synthesis of a potent small-molecule inhibitor 

of the target, preclinical validation, and 

demonstration of remarkable clinical benefits. 

Progress in the treatment of gynecologic 

cancers is likely to result from the 

introduction of novel drugs against specific 

molecular targets that are implicated in the 

growth and malignant behavior of cancer 

cells. Many such drugs are currently in 

various stages of development. The targets 

include growth signaling tyrosine kinases, cell 

cycle regulation, angiogenesis, apoptosis, and 

others. In setting priorities for therapeutic 

development, the members of the breakout 

group made two assumptions. First, all of the 

important targets for cancer treatment have 

not yet been discovered, which presents a 

great opportunity. Second, efficient clinical 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 35 
testing for the hundreds of expected agents 

against known and future targets repre

sents a major challenge to the oncology 

community. 

RESEARCH PRIORITIES 

The two major priorities in drug discovery 

and development for gynecologic cancers 

are relevant to all three major gynecologic 

cancers. Special opportunities exist in cervical and ovarian cancer research to serially 

sample specimens to define molecular targets and genetic determinants of response 

to therapies. 

Priority 1: Identify and validate key 

molecular targets for therapies. 

a. Support for national resources for tissue 

acquisition and banking should be 

markedly increased. 

Rationale 

Recent technologic developments permit 

analysis of all the expressed genes in 

tumor cells. It is widely believed that 

the pattern of gene expression in a 

particular tumor determines its 

aggressiveness, likelihood of metastasis, 

response to therapies, and potential to be 

cured. Fresh tissue is required for gene 

expression analysis. Currently, only 

one-third to one-half of specimens in the 

Cooperative Human Tissue Network 

sponsored by the National Cancer 

Institute (NCI) are suitable for studies 

requiring intact RNA. Furthermore, 

only a very small percentage of tumor 

specimens are obtained from patients 

who are currently entering clinical trials 

and for whom there are clinical data 

associated with the tissue samples. 

Specific Recommendations 

• More and better tissues should be 

acquired, appropriately stored, and 

annotated. This will require funding of 

key personnel at the centers that are 

the major contributors of tissues to the 

network. 

• Serial sampling of specimens should 

be supported in clinical trials for 

evaluation of molecular factors 

contributing to response and 

resistance. 

b. Preclinical models of gynecologic cancers 

should be developed for validation of 

targets and testing of therapeutic agents. 

Rationale 

Currently there are very few animal 

models for gynecologic cancers, and none 

that recapitulate the behavior of the 

human diseases. Such models might 

enable genetic manipulations for 

validation of targets and testing of new 

targeted therapeutic agents. 

Specific Recommendations 

Major incremental funding should be 

provided to establish models of 

gynecologic cancers. These models might 

include murine syngeneic tumors, 

orthotopic and non-orthotopic human 

xenografts, transgenic mice, and other 

systems. They should be representative of 

the diversity of these diseases and should 

be suitable for validation of therapeutic 

targets and new drugs. 

c. Gene expression profiling of RNA and 

proteins (genomics and proteomics) 

should be systematically applied in 

36 Report of the Gynecologic Cancers Progress Review Group 
clinical specimens and tumor models of 

gynecologic cancers. 

Rationale 

Data from recent and ongoing clinical 

trials in ovarian cancer should reveal 

genes or clusters of genes that are related 

to more malignant behavior, pathologic 

subtypes, and drug sensitivity versus 

resistance. Localized cancers of the 

cervix are anatomically accessible with 

minimally invasive procedures and thus 

represent a suitable clinical model for 

serial sampling of tumors during 

therapies. Ovarian cancers often provide 

an opportunity to obtain serial samples 

of tumor at diagnosis and subsequent 

surgeries, although “second-look” 

operations are not usually performed as 

standard procedures. 

Specific Recommendations 

• Funding mechanisms should be 

introduced for translational studies in 

clinical trials that do not require—as 

they currently do—a grant review 

and implementation process of 8 

months or longer. 

• Trials should be solicited of serial 

tumor sampling of locally advanced 

cervical cancer in the context of new 

therapeutic development. 

Priority 2: Optimize therapeutic clinical 

trials in gynecologic cancers. 

This priority presents a major challenge 

because of the large and increasing number 

of drugs available for development and the 

relatively limited number of participants in 

clinical trials. Optimization of therapeutic 

clinical trials in gynecologic cancers will be 

furthered by the approaches discussed next. 

a. Develop and implement surrogate markers 

for drug efficacy in clinical trials of new 

and existing agents. 

Rationale 

Large numbers of targeted therapies will 

be emerging in the next 5 years. The lack 

of reliable models requires efficient 

clinical testing. We must be able to 

rapidly address these questions: Is the 

drug getting to the target? Is it affecting 

the target as planned? Is the target 

interaction producing the desired effect? 

Specific Recommendations 

• Increase support for translational 

endpoints in clinical trials. Such 

support may include tumor tissue 

profiles, serum markers, and novel 

imaging technologies. The NCI 

should focus on barriers to these trials: 

patient accrual, physician reluctance, 

regulatory burdens, infrastructure 

support. The real costs of acquiring 

tissues and performing assays should 

be covered. 

• Spearhead research efforts in 

discovery and implementation of 

intermediate endpoints of effects 

of (often cytostatic) targeted 

interventions. 

• Foster broader use of pharmacokinetic 

and pharmacodynamic analyses in 

both early and late clinical trials 

through modeling with limited 

sampling techniques, quantitative 

and validated imaging, and genomic 

signatures of drug effect. 

b. Facilitate patient and physician 

participation in clinical trials of new 

drugs. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 37 
Rationale 

Only 2 to 3 percent of patients with 

gynecologic malignancies enter clinical 

trials. Even in Cancer Cooperative 

Groups, the bulk of accrual is accounted 

for by a small proportion of the 

physician membership. Barriers include 

lack of information to patients, lack of 

interest and information on the part of 

practicing physicians, economic 

disincentives to physician participation, 

lack of infrastructure support, consent 

requirements which go beyond those 

essential to informing patients of risks, 

benefits, and procedures. 

Specific Recommendations 

• Increase direct marketing of clinical 

trials to patients and physicians 

through a targeted public education 

effort with the participation of 

physician and patient advocate 

groups. 

• Increase physician education on 

clinical trials through engagement of 

physician organizations. 

• Direct funds to infrastructure support 

for physician participation in clinical 

trials. 

• Address regulatory obstacles through 

central institutional review boards 

and simplified consent procedures 

and reporting requirements. 

c. Develop pharmacogenomic approaches 

to predict drug response and toxicity. 

Rationale 

Variability in patients’ responses to 

therapy reflects differences in genetic 

make-up as expressed in quantitative and 

qualitative differences in gene products. 

These differences may be detected at the 

level of DNA, RNA, or protein through 

the application of novel technologies. 

Currently the purview of select academic 

and commercial sites, these powerful 

analyses have the potential to identify 

patients at risk of toxicity, patients in 

whom the intervention may work, and 

even the doses that are likely to be needed 

for efficacy. 

Specific Recommendations 

• Support (rapidly and without burdens 

of paperwork) the application of these 

techniques to samples obtained in 

clinical trials. 

• Limit the increasing consent burden 

that is a growing deterrent to such 

studies. 

d. Make new drugs available to patients with 

gynecologic cancers. 

Rationale 

The testing of new agents in gynecologic 

cancers is often delayed because these 

cancers are less prevalent than some other 

cancer types. The early clinical trials step 

will be a barrier to the investigation of 

promising targeted therapies in coming 

years. The large number of promising 

candidate molecules demands that a 

reevaluation of this system be undertaken. 

In parallel, growing numbers of patients 

who are aware of opportunities to 

participate in clinical trials will create a 

widespread demand for clinical trials. 

This demand should be met by increasing 

access to novel treatments for patients 

with gynecologic malignancies. 

Specific Recommendations 

• Make the evaluation of novel agents in 

gynecologic cancers a priority early in 

38 Report of the Gynecologic Cancers Progress Review Group 
the course of development of new 

drugs. 

• Implement physician and patient 

education to ensure enrollment in 

clinical trials early in the course of 

the disease (first, second, or third 

line), rather than referral after the 

failure of numerous marginally 

effective therapies. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 39 
Immunology 

Co-Chairs: Peggy A. Crowley-Nowick, Mary (Nora) Disis, and Douglas R. Lowy 

Participants:

Terri Cornelison Kevin G. Osteen Cornelia Trimble 

Ralph S. Freedman Martha C. Romans Judith Wolf

Kimberly Leslie Ellen Sheets 

BACKGROUND: STATE 

OF THE SCIENCE 

The immune system plays a role in 

modulating the growth of tumors in animal 

models. Ovarian, cervical, and endometrial 

cancers can serve as model tumor systems to 

evaluate immunologic questions that may be 

translatable to other tumor types. 

For example, the peritoneum of ovarian 

cancer patients is extraordinarily immunologically active. Ascitic fluid is rich in both 

lymphocytes and antigen-presenting cells. 

However, cancer cells grow despite this rich 

immune environment. Ovarian cancer offers 

an optimal model system for investigating 

immunosuppressive factors induced by the 

tumor or even by immune cells. 

Cervical cancer also offers a model 

immunologic system. Human papillomavirus (HPV) infection is the main etiologic 

factor in cervical cancer. Cervical cancer 

is a primary model for assessing the 

development of mucosal immunity. The 

initiation and maintenance of antigenspecific immune responses at the mucosal 

surface is necessary for the eradication of 

precursor and progressive cervical lesions. 

Principles defined in the generation and 

evaluation of mucosal immunity in the 

development of cervical cancer could be 

directly applied to other mucosal-based 

malignancies, such as oral cancer or colon 

cancer. 

Finally, hormonal influences may affect the 

immune response. The endometrial cancer 

model offers a system for evaluating the role 

of estrogen and progesterone in influencing 

the immune microenvironment. Studies 

performed in this area could have direct 

application to hormone-driven tumors such as 

breast and prostate cancers. Thus, evaluation 

of immunity in gynecologic tumors will not 

only advance the development of new 

therapies for the treatment of these diseases, 

but will also establish paradigms of immune 

evaluation applicable to other human 

malignancies. 

Patients with gynecologic cancers are being 

treated with immune-based therapies with 

mixed clinical results. Immunologic 

treatment will play a major role in the clinical 

treatment of gynecologic cancers. Effective 

translation of immune-based therapy can 

occur only if the underlying mechanisms of 

the immune response are better understood 

and defined. 

Clearly, all the components needed to 

stimulate immune responses—for example, 

APC and T cells—are present in the 

peritoneum of ovarian cancer patients. 

However, T cells specific for ovarian cancer 

cells in the peritoneum are detectable at only 

very low precursor frequencies. Preliminary 

studies demonstrate that both tumor and 

immune system cells may be involved in 

limiting the cancer-specific immune response; 

40 Report of the Gynecologic Cancers Progress Review Group 
however, the relative role of each remains 

poorly defined. In addition, no ovarian 

cancer-specific tumor antigens have been 

defined to allow specific laboratory 

assessment of the immune response. 

Cervical cancer may have the potential to be 

eradicated via the development and 

implementation of effective HPV vaccines. 

However, the steps required for the initiation 

of an effective immune response at the 

mucosal surface are not yet defined. 

Definition of vaccine strategies that would 

stimulate effective T cell and humoral 

immunity must be developed and rapidly 

tested. 

Finally, the uterus is an immunologically 

active organ. Other benign conditions such 

as endometriosis and pregnancy are present, 

in part, due to modulation of immunity. The 

effect of hormones on the initiation or 

augmentation of immunity has not been 

studied systematically. In addition, 

principles defined in related disorders are 

not being applied to the study of endometrial 

cancer and could rapidly advance our 

knowledge base. 

In summary, it is critical to study the 

endogenous immune response that occurs in 

patients with gynecologic malignancies. 

First, ovarian, cervical, and endometrial 

cancers each present unique immunologic 

problems and represent model systems for 

establishing principles that may be applied 

to other malignancies. These tumors are 

models because human material is easily 

accessible, both systemically and at the site 

of tumors (ascites and cervical washings). 

Second, immune-based therapies have 

proven utility in the treatment and 

prevention of disease, particularly the use of 

HPV vaccines in cervical cancer. Finally, 

effective treatments for advanced-stage 

ovarian, cervical, and endometrial cancers 

are not available. Harnessing the immune 

system for treatment offers a new translational modality for gynecologic cancer 

therapeutics. 

QUESTIONS AND CHALLENGES 

OVARIAN 

Which components of the immune and tumor 

microenvironments initiate regulatory effects 

on the tumor-specific immune response? 

• Define the immune components in the 

peritoneum of patients with ovarian 

cancer and determine the functional 

defects as compared with components in 

the periphery and in non-tumor-bearing 

hosts. 

• Determine tumor antigens involved in 

ovarian cancer to provide a model for 

evaluation and dissection of the 

endogenous immune response. 

• Determine the role ascitic fluid plays in 

modulation of immune response. 

CERVICAL 

What are the steps in the initiation of effective 

mucosal immunity, based on the phenotype 

and clinical efficacy of the generated immune 

response? 

• Define an effective anti-viral (HPV) 

immune response. 

• Define an effective anti-tumor immune 

response. 

• Determine a vaccine strategy that would 

stimulate biologically relevant anti-viral 

and/or anti-tumor immunity. 

• What are the immunologic problems in 

the development of prophylactic versus 

therapeutic vaccines? 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 41 
• Is HPV a sufficient target or are other 

tumor antigens involved in the malignant 

transformation needed for tumor 

eradication? 

ENDOMETRIAL 

What is the regulatory role of steroid 

hormones in influencing the generation of 

immunity to endometrial cancer? 

• Define differences in local immunity 

between the hyperplastic and atrophic 

uterus. 

• Characterize the hormonal influence in 

local cytokine production and regulation 

of immunostimulatory molecules on 

APC and immune effector cells. 

• Identify immunogenic proteins in 

endometrial cancer and determine 

whether hormone environment effects 

their expression. 

RESEARCH PRIORITIES 

Priority 1: Focus on the characterization 

and function of the immune micro-environment in the genital tract. 

Ovarian: Immunosuppressive effects of the 

tumor and regulation of immune effectors 

Cervical: Influences on the generation of 

effective mucosal immunity 

Endometrial: Role of the hormone environment in regulating immunity 

Priority 2: Advance the clinical translation 

of immune-based therapies to both target 

specific antigens and correct or overcome 

defined immune modulating defects. 

Clinical trials must be designed to evaluate 

biologic endpoints as a primary result. In 

addition, trials must seamlessly integrate 

laboratory evaluation. Human clinical 

trials can serve as the primary model for the 

evaluation of immune-based therapies. 

Priority 3: Define and expand the repertoire 

of tumor antigens for each of the gynecologic 

cancers. 

TUMOR-SPECIFIC PRIORITIES 

OVARIAN 

Priority 1: Increase basic science studies to 

determine the role of the peritoneal microenvironment in modulating the immune 

response at different stages of disease. Focus 

basic studies on discerning the differences in 

peripheral immune response versus local 

immune response in both ascites and at the 

tumor site. Define immune dampening factors 

secreted not only by the tumor but also the 

very cells stimulating the immune response. 

Priority 2: Define immunogenic proteins 

(i.e., tumor antigens in ovarian cancer). 

Target tumor antigens will provide some 

model systems for monitoring immune 

responses and defining immunogenic defects. 

The critical assessment of specific antigens 

through the ovarian disease process may 

minimize the need for the development of 

animal models for evaluation of immunity. 

Priority 3: Prioritize human clinical 

translational studies of immunologic agents in 

trials that have a strong correlative aspect. 

The human studies must be designed to 

answer basic biologic questions as a priority. 

These clinical trials may be intercalated into 

standard therapies to improve recruitment for 

novel therapies. 

CERVICAL 

Priority 1: Encourage studies to improve our 

basic understanding of mucosal immunity in 

the cervix. Prioritize the understanding of 

both endogenous factors (e.g., influences of 

hormones) and exogenous factors (e.g., 

42 Report of the Gynecologic Cancers Progress Review Group 
smoking and other pathogens) and their role 

in influencing mucosal immune responses. 

Define the differences between systemic 

immunity and the immune responses at the 

mucosal surface or site of neoplasia. 

Priority 2: Develop prophylactic and 

therapeutic vaccines and validate laboratory and biologic correlates for clinical 

response. 

Priority 3: Differentiate between the 

immune response to a virally infected cell 

and to a cancer cell. What are the 

differences between HPV-specific immunity 

and cervical cancer–specific immunity 

(temporal phenotype)? These differences 

include the antigenic repertoire as well as 

the phenotype of both T cell and humoral 

immunity generated at the site of disease. 

Studies would include the basics of immune 

responses needed for prophylactic versus 

therapeutic vaccines. 

Priority 4: Obtain immunologic profiles of 

women with cervical cancer to discern in 

whom chronic HPV infection develops and 

in whom it is eradicated. Profiling should 

be evaluated at both the cellular and the 

molecular levels. Studies should include 

population and epidemiologically based 

evaluation to link immune defects with other 

potential environmental concerns. 

ENDOMETRIAL 

Priority 1: Discern the effects of hormones 

on the immune system and the cytokine 

environment of the endometrium. Evaluate 

the differences in the immune microenvironment of atrophic and hyperplastic 

endometrium. Determine tumor antigens 

present in endometrial cancer and how 

hormones regulate them. 

Priority 2: Develop phase I clinical trials of 

immune-based therapies for the treatment of 

endometrial cancer. 

BARRIERS 

Numerous barriers impede the progress of 

elucidating tumor-specific immunity in 

gynecologic cancers, as well as our ability to 

develop new and effective immune-based 

therapies: 

• Unavailability of biologically relevant 

animal models for the evaluation of 

immunity in gynecologic cancers 

• Lack of emphasis on the translation of 

clinical strategies from other cancer 

therapies into gynecologic disease 

• Lack of defined immunologic endpoints 

for the readout and interpretation of 

clinical trials 

• Insufficient “cross-talk” between critical 

disciplines involved in the evaluation of 

immunity, such as basic immunologists, 

biologists, and gynecologic oncologists 

• Deficiency in the education of the community concerning the effects of HPV 

infection on health maintenance and the 

development of cervical cancer, limiting 

study accrual 

• Lesser incentive of patients with 

preinvasive disease, as compared with 

cancer patients, to participate in clinical 

trials 

• Lack of defined immunologic targets 

(i.e., tumor antigens) in gynecologic 

malignancies 

RESOURCES 

• Request for Application (RFA)-based P01 

mechanisms to fund groups of multidisciplinary investigators focused on the 

priority research topics 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 43 
• Increased funding for development and 

validation of immunoassays to establish 

correlates of clinical response 

• Support to fund extensive longitudinal 

analysis of baseline immune responses 

to tumor antigens and to assess immunologic memory or persistence of immune 

responses in patients undergoing 

immunomodulatory therapy 

• Infrastructure for community education, 

recruitment, and retention of patients 

with precancerous lesions in clinical 

trials for HPV vaccines 

• A standardized and validated system for 

the collection and storage of peripheral 

blood lymphocytes, sera, tissue, and 

genital tract secretions for the evaluation 

of tumor-specific immune response as the 

field develops and antigens are identified 

• Molecular target assessment and 

evaluation initiatives for gynecologic 

tumor antigens and programs to link 

scientists working on cell biology and 

array technology with immunologists to 

assist in the identification of potential 

target antigens 

• Immunologic advisory committee within 

the Cancer Cooperative Group system to 

aid in the rapid translation of biologically 

based therapies into phase II studies 

44 Report of the Gynecologic Cancers Progress Review Group 
Radiobiology 

Co-Chairs: Peggy Olive and Marcus E. Randall 

Participants: 

Carolyn M. Ballard Deborah Jaffe Groesbeck Parham 

Farrokh Dehdashti Charles Levenback Rivienne Shedd-Steele 

Michael A. Friedman Marc S. Mendonca Aaron Wolfson 

Hedvig Hricak David Mutch 

OVERVIEW AND STATE 

OF THE SCIENCE 

Radiation therapy plays an important role in 

the management of many patients with 

gynecologic malignancies, particularly 

cervical, endometrial, vaginal, and vulvar 

cancers. Although at present the role of 

radiation therapy in ovarian cancer is 

limited, this has not always been the case 

and should not be assumed to remain so. 

Because radiation therapy is a local 

treatment modality (although extended fields 

are feasible), it is worthwhile to recognize 

that failure to cure can result from either the 

inability of radiation therapy to produce 

local control or systemic failure outside the 

radiation-treated volume. In some cases, 

both patterns of failure are seen, and some 

data suggest that failure to control local 

disease can itself lead to systemic failure by 

providing clonogens for dissemination. 

Many questions remain regarding the 

determinants of intrinsic radiosensitivity. 

One therapeutic strategy would be to 

measure radiosensitivity at the initiation of 

radiation therapy, using this information to 

individualize a prescription that would 

favorably affect radiosensitivity, such as 

chemotherapy, specific chemotherapy 

agents, bioreductive agents, optimized 

radiation therapy fraction sizes, and so forth. 

Ultimately, correlations between gene 

expression and translation and intrinsic 

radiosensitivity are needed. Tumor 

heterogeneity and genomic instability are 

potential barriers to understanding that need 

to be overcome. 

Measurements of intrinsic radiosensitivity 

would facilitate research into methods of 

modifying it. For example, early data suggest 

that Cox-2 inhibitors might favorably impact 

radiosensitivity. If so, the concept of doseresponse relationship for microscopic disease 

might be found to be much more complex 

than currently realized. This would open 

broad new avenues for clinical research and 

would imply significant changes to currently 

accepted treatment methods and concepts. 

Optimum management of gynecologic 

cancers with radiation therapy requires an 

understanding of normal tissue tolerance. 

Specifically, the structure and function of 

organs such as the small and large intestines, 

rectum, and bladder must be preserved in a 

large majority of patients. Otherwise, the 

therapeutic ratio will tilt away from the use of 

radiation therapy. 

Attempts to ameliorate or limit radiation 

toxicity by using radioprotectors have been 

met with some success, but further research is 

needed. Also, clinicians have long had some 

qualitative understanding of the relationship 

between tolerance and volume of normal 

tissue treated. The use of three-dimensional 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 45 
imaging and treatment planning techniques, 

quantitative analyses of dose distributions 

(e.g., dose-volume histograms), and special 

treatment techniques such as intensitymodulated radiation therapy (IMRT) has 

yielded an increasing understanding of these 

relationships. Typically, these specialized 

treatment techniques “spread out” dose over 

larger volumes, giving lower doses to organs 

with less tolerance to radiation. The radiobiologic implications of giving lower doses 

of radiation therapy to larger volumes can 

and must be considered quantitatively. 

CERVIX 

Radiation therapy is the primary therapy for 

patients with tumors extending beyond the 

cervix. Given the reasonably high doses that 

can be delivered safely by using brachytherapy techniques, high rates of local 

control and cure are reproducibly obtained. 

Recent clinical trials have shown that 

concurrent chemotherapy, generally with 

platinum or platinum-based regimens, can 

further augment these outcomes. However, 

even with optimum radiation therapy and 

chemotherapy, about one-fourth of patients 

with stage II cancer and up to two-thirds of 

those with stage III cancer still die of their 

disease. 

Clinicians recognize a wide spectrum of 

individual tumor responsiveness to and 

curability with radiation therapy. Some 

trends in responsiveness and curability are 

seen. For example, certain histologies, such 

as small cell carcinoma and very poorly 

differentiated tumors, are generally very 

responsive to radiation therapy but have a 

significant rate of systemic dissemination, 

which impairs their curability. Patients with 

lower hemoglobins and lower tumor oxygen 

tensions probably have lower cure rates with 

radiation therapy. Patients with larger 

tumors fare more poorly than those with 

smaller tumors, such as unilateral versus 

bilateral stage IIB or IIIB, and stage II 

versus stage III. However, none of these 

clinically identifiable factors directly correlate 

with responsiveness to or curability with 

radiation therapy. Furthermore, only tumor 

oxygenation is potentially alterable after the 

diagnosis is made and treatment initiated. 

Tumor hypoxia is an area of considerable 

interest. In fact, a current Gynecologic 

Oncology Group trial is evaluating the 

potential of hemoglobin maintenance above 

12 g to improve outcomes compared with 

hemoglobin maintenance above 10 g. 

Both transfusions and growth factors 

(erythropoietin) are used in the 12-g arm 

of this study. However, this is a relatively 

crude approach because it does not directly 

assess for tumor hypoxia. Furthermore, 

hypoxia is not an all-or-none phenomenon, 

but a continuum. Hypoxia markers such as 

pimonidazole and EF5 are possible routes to a 

better understanding of patient-specific tumor 

oxygenation status. 

It should be recognized that unsuccessful 

attempts to overcome tumor hypoxia in 

cervical cancers have been previously made 

using hypoxic cell sensitizers, carbogen and 

oxygen breathing, and densely ionizing 

radiations. At present we have a poor 

understanding of why these maneuvers lacked 

efficacy. Possibly it is simply a matter of not 

being able to select those patients who would 

benefit from these approaches, thus diluting 

any potential gain. More likely, it is much 

more complicated. For example, it is known 

that the tumor vasculature is abnormal both 

anatomically and physiologically. Therefore, 

it is quite possible that systemic attempts to 

alter the tumor microenvironment (e.g., tumor 

oxygenation status) will yield inconsistent and 

uninterpretable results. Perhaps this is an area 

for investigation and therapeutic intervention 

(e.g., nicotinamide). Also, the lack of 

efficacy of therapeutic strategies directed at 

overcoming tumor hypoxia does not necessarily imply failure of all such strategies. 

Therefore, the potential of bioreductive drugs 

46 Report of the Gynecologic Cancers Progress Review Group 
such as tirapazamine continues to be 

investigated. 

Separate, more logistical problems with 

identification of hypoxic tumors (and other 

tumor-specific factors with therapeutic 

implications) concerns the invasiveness of 

procedures required to establish tumor 

oxygenation status (Eppendorf electrode) 

and tumor heterogeneity. Imaging tools, 

recognition of gene expression patterns 

consistent with hypoxia, or identification of 

endogenous factors, if validated, could be 

useful in individualizing therapy based on 

tumor-specific characteristics. Furthermore, 

there is some question regarding the 

importance of tumor oxygenation status at 

the time of diagnosis and/or initiation of 

therapy, since this variable is almost certain 

to change significantly over the course of 

fractionated radiation therapy. 

Although some questions remain, recent 

clinical trials have shown improvement in 

local control and survival by combining 

chemotherapy with radiation therapy for 

most patient populations with cervical 

cancer. The biologic basis of this is unclear 

and needs further study. One possibility is 

that chemotherapy affects the fidelity of 

radiation repair through one or more 

mechanisms, including lesion recognition, 

aberrant signaling, inaccurate repair, and 

others. Similarly, ionizing radiation 

could be sensitizing tumor cells to the 

antiproliferative effects of the chemotherapy agents, accounting for the synergy 

observed clinically. Given the widely 

accepted clinical utility of combining 

chemotherapy and radiation therapy in 

patients with cervical cancer, it is surprising 

that we know so little about the mechanisms 

of these interactions. Such information 

could suggest additional, more effective 

ways in which to exploit the advantages of 

combined therapies. One potential line of 

investigation concerns measuring levels of 

DNA-cisplatin adducts and correlating these 

findings with clinical outcomes. 

The identification of accelerated repopulation 

of tumor clonogens during fractionated 

radiation therapy has had an impact on the 

radiotherapeutic management of some tumor 

sites such as head and neck cancers. In 

cervical cancer, it is likely that there are 

similar opportunities to favorably impact 

outcomes using treatment strategies such as 

altered fractionation schemes, optimally timed 

treatment combinations, and others. We need 

a better understanding of the genetic basis of 

tumor growth kinetics, including factors 

affecting gene expression and translation. 

Again, for treatment alterations and concepts 

to have the potential to improve treatment, it 

will obviously be necessary to determine 

patient- and tumor-specific kinetic information so that appropriate patient and treatment 

selection can be undertaken. A significant 

barrier to this concept (and all radiobiologic 

concepts) is the phenomenon of tumor 

heterogeneity and genomic instability. In 

other words, the treatment target(s) are 

moving and changing between different 

patients and even within the same patient and 

her tumor. Hopefully, patterns will emerge 

that can be identified and exploited clinically. 

ENDOMETRIAL AND OVARIAN CANCERS 

Radiation therapy plays a largely adjunctive 

role in early-stage endometrial cancer, which 

fortunately makes up the vast majority of 

these tumors. However, treatment outcomes 

remain poor for most patients with advanced 

disease or certain high-risk tumor types. For 

these patients with unfavorable disease, 

multiple approaches with radiation therapy 

have been used, with only moderate success. 

Although radiation therapy is clearly a very 

active agent with demonstrably high response 

rates in endometrial and ovarian cancer 

patients with measurable disease, barriers to 

its successful use in unfavorable and lateAppendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 47 
stage endometrial cancer include the 

propensity of this subgroup of patients to 

have hematogenous or peritoneal tumor 

dissemination and the limited normal tissue 

tolerances of large volumes (particularly 

liver and small bowel) treated with radiation 

therapy. 

Radiation therapy has been used extensively 

for ovarian cancer in the past, and it is 

known to have significant activity and 

curative potential in identifiable subsets of 

patients. However, its use in curative 

management has largely been curtailed as 

cytotoxic agents and combinations with high 

response rates have been identified. Even 

so, high and even complete response rates 

with modern chemotherapy fail to cure the 

vast majority of women diagnosed with this 

disease. Given the demonstrable singleagent activity of ionizing radiation, it is 

reasonable to postulate that its use should be 

furthered studied, at least in combination 

with other active agents. Again, tumor 

biology–based predictive assays could help 

direct treatment and further study. 

The Gynecologic Oncology Group has 

recently completed a direct comparison of 

cytotoxic chemotherapy versus wholeabdomen radiation therapy in patients with 

stages III and IV disease. The results of this 

study are not yet available, but it is clear that 

the majority of women are still not being 

cured of their disease, despite these 

aggressive therapies. The use of combinedmodality therapy, so common and so 

promising in other diseases, has been only 

minimally studied in endometrial cancer. In 

the limited clinical efforts to combine 

systemic therapy with radiation therapy, no 

translational research has been undertaken to 

understand issues of radiosensitization 

and/or chemosensitization. This leads to the 

current situation in which only empirical 

approaches to combined-modality therapy 

can be considered. 

Similarly, before the taxane era in ovarian 

cancer management, the Gynecologic 

Oncology Group conducted a combinedmodality study of limited chemotherapy 

followed by whole-abdomen hyperfractionated radiation therapy. The results from 

this study suggested that outcomes in disease 

status were reasonably equivalent to those 

achieved with more prolonged chemotherapy 

regimens. Furthermore, this study yielded 

information about integrating treatments 

including surgery, dose-response relationships, and appropriate radiation therapy 

volumes and treatment delivery. As taxanes 

became integrated into the standard cytotoxic 

regimen, no further studies incorporating 

radiation therapy have been undertaken in 

ovarian cancer; however, other clinical data, 

particularly from Europe, strongly suggest the 

potential of combined-modality therapy to 

improve outcomes over chemotherapy alone. 

Very little success has been achieved in 

attempts to understand the mechanisms of 

radioresistance and radiosensitivity in 

endometrial and ovarian cancers. It follows 

that we know very little about how to modify 

radiation response. It is known that the doseresponse relationship for microscopic disease 

is a multifactorial rather than a consistent 

relationship, accounting for the continuum 

of responses and control rates observed 

clinically. Possible factors involved in this 

phenomenon include inherent clonogen 

radiosensitivity, the number of clonogens, 

tumor microenvironment, patient immunologic status, and others. 

In ovarian cancer and some variants of 

endometrial cancer, we need to think more 

critically about treatment strategies in which 

radiation therapy is used in novel ways that 

might be more effective and with less 

toxicity. For example, one concept is to 

use “intermittent” radiation therapy along 

with cycles of chemotherapy, thinking 

conceptually of ionizing radiation as simply 

48 Report of the Gynecologic Cancers Progress Review Group 
another cytotoxic agent used in combination 

with other cytotoxic agents. This idea 

would require a change from thinking of 

radiation therapy as a continuous course of 

daily treatment. In this schema, radiation 

therapy would be used intermittently and at 

lower doses. Conceptually, this approach 

would allow the use of a very active single 

agent, avoid blind adherence to previous 

dose and time concepts, and entail the use of 

therapy that would be potentially effective at 

lower doses, possibly lowering toxicity 

rates. Well-thought-out clinical trials are 

needed in this area. 

Another novel concept being studied in 

a clinical trial entails the use of intraabdominal radionuclides and vaginal cuff 

brachytherapy in stages I through IIIA 

serous papillary endometrial carcinoma. 

This approach potentially treats microscopic 

disease within the entire abdominal cavity 

without the potential acute and late toxicities 

of whole-abdomen external-beam radiation 

therapy from standard doses. A next step 

could be the integration of chemotherapy or 

biologic therapies into this regimen. For 

example, some laboratory data suggest that 

combining intraperitoneal cisplatin with 

radioactive phosphorus-32 kills ovarian 

cancer cells synergistically. Early clinical 

work using this combination and other 

intraperitoneal isotopes has been promising 

but largely ignored. 

RESEARCH PRIORITIES 

Priority 1: Use current and future technologies to gain a better understanding of tumor 

biology through multiple assays that are related or potentially related to the efficacy of 

radiation therapy, including hypoxia, intrinsic radiosensitivity, growth kinetics, gene 

expression/suppression, and angiogenesis. 

• Develop a computerized, integrated tumor 

biology database that permits sharing of 

information and collaboration between 

investigators to combat overly focused 

“reductionism” and promotes interaction 

in biologically oriented cancer and 

radiation biology research. Potentially, 

this would move us toward clinically 

relevant predictive assays based on best 

practices and, possibly in time, 

standardization. 

• Recognize that tumor biologic parameters 

potentially are typically measured at 

only one point in time (typically at the 

beginning of treatment). We must 

discover how these parameters change 

with time in surviving cells, either in 

terms of the natural history of the disease 

or in response to treatment, such as 

fractionated radiation therapy. 

• Establish tissue banks and cell lines to 

investigate tumor biologic markers that 

might function as predictive assays. 

This will permit both prospective research 

and retrospective validation of these 

parameters based on patient outcome 

(e.g., evaluate why treatment failed in 

some patients and not in others). Markers 

may also serve as molecular targets. 

• Correlate laboratory-derived tumor 

information with noninvasive types of 

functional predictive assays, including 

endogenous markers, imaging techniques, 

and so forth. 

• Investigate clinically relevant methods to 

overcome or modify radiation resistance 

as prospectively identified through 

laboratory studies of fractionation, dose 

rate, treatment combinations, and so forth. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 49 
Rationale 

The goal is individualized and optimized 

therapy based on patient- and tumor-specific 

characteristics that can be identified at the 

time of diagnosis. The concept of optimized therapy might well require changes 

in tumor biology during treatment, raising 

the question of a “dynamic” and individualized approach to treatment with 

radiation therapy. 

Discussion Points 

a. Hypoxia—relationship to angiogenesis, 

pH, redox potential? 

• Measurement—pimonidazole, EF5, 

HL91, and so forth 

• Endogenous markers, non-invasive 

assessment vs. direct assessment 

• VEGF, HIF-1alpha, Glut-1 

• EPO, carbogen 

• Blood flow alterations (e.g., 

nicotinamide) 

• Tumor vasculature abnormal 

anatomically and physiologically 

• Surrogate for other effects increased 

metastatic potential 

• Promotes mutations 

b. Growth kinetics 

• Ki67, IUdR incorporation, PCNA 

• Accelerated repopulation 

• Overall treatment time 

• Effects of cell cycle agents 

• Importance of tissue banks and cell 

lines with varying proliferative 

characteristics 

c. Intrinsic clonogen radiosensitivity 

• Two ways to kill cell: alpha (single 

hit), beta (double hit); different effects 

at different dose rates and fraction 

sizes, different repair characteristics 

• DNA arrays 

• Functional assays 

Priority 2: Understand better the biologic 

basis of combination therapies. 

• Gain a better understanding of the 

mechanism(s) of action of currently used 

combination therapies (platinum–radiation 

therapy). Can they be combined more 

effectively? How can we capitalize on 

“resistance”? 

• Evaluate new approaches (“new 

paradigm”) to the use of radiation therapy 

in non-conventional ways. For example, 

radiation therapy could be used in a 

manner more akin to a chemotherapy 

agent—concurrently with a course of 

chemotherapy, such as every 3 weeks— 

instead of as a single continuous course 

of treatment. In addition, there has been 

no systematic study of the use of 

chemotherapy concurrently with lowdose-rate brachytherapy. This needs to be 

investigated because there are several 

potential applications in gynecologic 

cancers. Radiobiologic studies can 

potentially guide clinical investigations. 

• Investigate additional ways in which to 

combine therapies to optimize outcomes, 

for example, schedule dependence, new 

agents, combinations of agents, and so 

forth. Ideally, the efficacy of combined 

regimens will be predictable on the basis 

of laboratory parameters. 

50 Report of the Gynecologic Cancers Progress Review Group 
• Identify tumor characteristics correlating 

with which tumors are most amenable to 

specific combinations of therapies. (This 

recommendation overlaps with Priority 

1.) Gain an understanding of the 

biologic basis of multiple combination 

therapies. 

• Investigate the potential and role of gene 

therapies with radiation response 

elements in the radiotherapeutic 

management of gynecologic cancers. 

• Evaluate the potential of agents that 

alter either the dose-response relationship (equivalent response at lower dose) 

or dose-toxicity relationship (e.g., radioprotective agents). 

Rationale 

The goal is individualized and optimized 

therapy combinations, when appropriate, 

based on patient- and tumor-specific 

characteristics which can be identified at the 

time of diagnosis in order to improve 

outcomes. 

Discussion Points 

• Mechanisms of cisplatin–radiation 

therapy sensitization (e.g., correlation of 

DNA adducts with outcome, effects on 

fidelity repair of radiation damage, 

patient/tumor variability) 

• Concurrent platinum-32 

• Variability in response—uptake, MDR, 

kinetics 

• Effects on normal tissue 

• Sequencing/timing 

Priority 3: Develop novel radiation 

treatment strategies designed to improve 

response and control rates and decrease 

acute and late toxicities. This will require a 

paradigm shift in relation to how radiation 

therapy is used and combined with other 

therapies, as well as support from Cancer 

Cooperative Groups and Cancer Centers that 

are interested in gynecologic cancers. 

• Evaluate strategies that can favorably alter 

dose-response relationships. For example, 

if radiation in combination with another 

agent (e.g., Cox-2 inhibitors) can 

reproducibly sterilize microscopic disease 

at doses lower than 45 Gy, this will have 

major implications for the use of higher 

doses to smaller volumes, will make 

radiation therapy more efficacious at 

larger volumes, and so on. (This 

recommendation overlaps with Priority 2.) 

• Study novel ways of using radiation 

therapy, particularly in combination with 

other cytotoxic or biologic therapies, 

sequencing/timing issues, “intermittent” 

radiation therapy with courses of 

chemotherapy, and concurrent 

chemotherapy with low-dose-rate 

brachytherapy. 

• Work toward a more quantitative 

understanding of the relationship between 

treatment volume and tissue tolerance 

through dose-volume histogram analysis, 

and so forth. 

• Better understand the biology of different 

radiation fractionation schedules, brachytherapy, radiation effects on normal tissue, 

and so forth. (This recommendation 

overlaps with Priority 1.) 

• Study the potential of technological 

approaches to improvements in radiation 

therapy by more accurate definitions of 

target volume, use of “dose sculpting,” 

intensity-modulated radiation therapy, and 

so forth. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 51 
• Strengthen education and training of 

health professionals in the area of 

gynecologic cancer treatment with 

radiation, with particular attention to the 

needs of nonindustrialized countries, 

research into electronic media–based 

instruction and testing, and movement 

toward a reproducibly high standard of 

radiation therapy capability that can be 

effectively communicated and implemented. Specifically, scientific and 

clinical partnerships with nonindustrialized countries could be 

considered that could answer research 

questions in a more timely way while 

providing access to improved therapies 

to underserved populations. 

Rationale 

The goal is to optimize treatment selection 

and delivery utilizing biologic and technical 

advances. 

Discussion Points 

• HIV status 

• Photodynamic therapy 

• Importance of clinical trials 

• Recognition of overlap between 

technical science and biologic science 

• HPV status 

BARRIERS 

• Currently there is a lack of a dedicated, 

versatile, centralized tissue bank 

(associated with clinical outcomes) that 

will facilitate a prospective analysis of 

tumor biology, assessment of correlations with radiation response, and 

understanding of potential of combination therapies and other novel 

therapeutic approaches. Such a 

centralized resource would facilitate 

retrospective correlative studies designed 

to assess tumor characteristics associated 

with treatment failure. In addition, similar 

considerations would suggest the 

establishment of multiple tumor cell lines 

of various radiobiologic characteristics 

that can be shared among investigators. 

• There is a huge problem with tumor 

heterogeneity and genomic instability. 

These realities are typically ignored in 

tumor biology research in the interest of 

simplicity. This suggests the need for 

repeated sampling of patients’ tumors 

over the course of treatment and the 

course of their disease. Potential barriers 

include patient acceptance and the 

logistical difficulties of repeated 

sampling. 

• There is a large number of disparate 

methods for multiple assays, for example, 

hypoxia. The relative lack of uniformity 

of approach and validation of markers and 

methodology is a significant barrier to 

progress. 

• It is also very difficult to perform combined predictive assays in the same 

patient/tumor, since sample size can be a 

significant problem. 

• It is possible that the relationship between 

the Radiation Branch of the National 

Cancer Institute (NCI) and the NCI, more 

generally, should be rethought. This 

would potentially increase the awareness 

of the need for radiobiologically oriented 

and technologically oriented research, 

foster collaborations with other scientists, 

and result in removal of some current 

barriers to research. 

• The cost of methodologies, including 

imaging techniques, tissue bank, and cell 

line maintenance, are significant and 

operates as a barrier to progress. 

52 Report of the Gynecologic Cancers Progress Review Group 
RESOURCES 

• A tissue bank and tumor cell lines 

characterized for radiation response and 

other relevant endpoints. Ideally, this 

will include sequential biopsies over the 

course of treatment as well as samples 

from recurrent tumors. Furthermore, to 

maximally benefit from this research 

material, the tissue and cell lines should 

be potentially linkable to patient 

information regarding treatment and 

outcomes. 

•. A program of basic research to define 

the tumor properties that have an impact 

on and predict radiation sensitivity, 

response, and outcomes (hypoxia, 

growth kinetics, angiogenesis, apoptosis, 

intrinsic radiosensitivity). 

• There is a need to forge alliances 

between groups to work with the same 

tumor samples but with interests or 

abilities to measure different predictive 

endpoints. 

• There is a need to better recognize and 

correct the serious lack of understanding 

of the mechanisms of action of radiation 

combined with chemotherapy, biological 

therapy, and gene therapy in the treatment 

of gynecologic cancers. This will require 

the initiation of a well-supported program 

of basic tumor biology research focused 

on this issue and will have the potential of 

suggesting different and better treatment 

combinations. 

• Additional support is needed for new 

technologies and approaches aimed at 

improving dose distribution, target 

volume accuracy, and normal tissue 

tolerance in gynecologic cancers. 

• Initiatives to strengthen education and 

training of health professionals in 

gynecologic cancer treatment in the 

United States and in developing nations 

should be undertaken with the goal of 

moving toward a reproducibly high 

standard of clinical radiation therapy. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 53 
Laboratory and Clinical Models 

Co-Chairs: Ronald Alvarez and Thomas C. Hamilton 

Participants: 

Jeffrey Arbeit Loretta Itri James Tate Thigpen 

Louise Chow Robert Lenkinski Barbara Vanderhyden 

Lora Hedrick Ellenson Cheryl Marks 

Patricia Goldman John McPherson 

Paul Goodfellow Karl Podratz 

Silvia Curtis Hewitt M. Sharon Stack 

BACKGROUND 

A variety of gynecologic cancer models are 

in various stages of development. A critical 

question that needs to be addressed is the 

relevance of these various models to human 

gynecologic cancers. Unless models 

recapitulate the human cancer they were 

designed to model, results from modeling 

will be irrelevant to cancer prevention, 

detection, and treatment. 

Following is a brief overview of current 

models for ovarian, cervical, and 

endometrial cancer. The strengths and 

weaknesses of these models are also 

described. 

OVARIAN CANCER 

Various models of ovarian cancer are under 

development. These include in vitro models 

that employ spontaneous and genetically 

transformed ovarian surface epithelial cell 

lines, as well as in vivo rodent and avian 

models that employ xenografts, induce 

spontaneous cancers, or utilize gene transfer 

and transgenic technology. Some models, 

such as transgenic in vivo models, have 

come about only in the past few years. One 

current strategy involves crossing two 

transgenic strains to produce one that has 

expression specific to ovarian surface 

T. C. Wu 

Richard J. Zaino 

epithelial cells. Another involves screening 

for candidate oncogenes by isolating cultures 

of epithelial cells, transfecting with the 

candidate oncogene, and reintroducing the 

cells into a mouse or rat. 

Strengths 

• Epithelial in nature 

• Controlled and controllable systems 

• Employ candidate genes involved with 

carcinogenesis 

Weaknesses 

• Variations in histologic subtypes not 

recapitulated 

• Inherent differences in human ovarian 

biology may frustrate the study of specific 

interactions (lack of post-reproductive 

phase in mice or differences in ovulation 

biology in avian models) 

CERVICAL CANCER 

Models of cervical cancer include several that 

examine human papillomavirus (HPV), which 

has been implicated in the overwhelming 

majority of cervical cancers. In vitro model 

systems include a three-dimensional 

54 Report of the Gynecologic Cancers Progress Review Group 
organotypic culture of stratified epithelium, 

which allows for direct comparison with 

patient specimens. The cultures can also be 

transfected with specific HPV oncogenes 

and can be used to test the effects of 

therapeutic drugs, the interactions with other 

microbes, and the effect of other 

phenomena, such as wound healing. 

Cervical cancer mouse models are also 

under study, including a transgenic model in 

mice that express the HPV genes E6 and E7, 

which have shown to be necessary (but not 

sufficient) for cervical carcinogenesis. This 

model differs from human disease in several 

ways, however: it exhibits no intraepithelial 

lymphoid aggregates, model cancers remain 

microscopic and confined to the cervix, 

cancer development requires chronic 

estrogen treatment, there is no metastasis, 

and model cancers may regress in the 

absence of estrogen. 

Strengths 

• Histologic similarities to human disease 

• Controlled and controllable systems 

• Utilizes HPV genes involved with 

carcinogenesis 

Weaknesses 

• Lack of immunocompetent models 

• Dependence upon hormonal 

manipulation 

ENDOMETRIAL CANCER 

Most mouse models for endometrial cancer 

are of endometrioid (type I) cancer, which 

has a significant estrogen component. There 

are no mouse models of serous (type II) 

endometrial cancer, which does not have a 

significant estrogen component. The two 

genetic models that are best developed are 

the phosphatase and tension homologue 

(PTEN) gene and the DNA mismatch repair 

models. All mouse models are limited due to 

the fundamental differences between the 

biology of the mouse and that of the human, 

including the estrus cycle in mice versus the 

menstrual cycle in humans, a limited postreproductive anestrus period in mice 

compared with that of humans, and 

anatomical differences. A hormonal mouse 

model of endometrial cancer produced 100 

percent penetrance but no metastatic disease; 

therefore, it is unclear whether the model will 

be useful for preclinical drug development. 

Strengths 

• Histologic similarities to human disease 

• Controlled and controllable systems 

• Similar etiology 

Weaknesses 

• Inbred animals may respond to genetic 

and environmental factors in a strain- or 

line-specific way (however, this may 

allow identification of genetic modifiers). 

• Inherent differences in endometrial 

biology may frustrate the study of specific 

interactions (lack of post-reproductive 

phase in mice). 

RESEARCH PRIORITIES 

Priority 1: Validate genetic, physiologic, and 

environmental pathways in current and future 

models. 

Rationale 

Gynecologic cancers are characterized 

by unique genetic, physiologic, and 

environmental processes that lead to 

carcinogenesis. It will be important to 

determine whether models, as they are 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 55 
developed, recapitulate these etiologic 

components. 

Priority 2: Validate histopathology in 

current and future models. 

Rationale 

Within each gynecologic cancer are multi

ple, heterogeneous histologic subtypes. It 

will be important to determine whether 

models recapitulate the histologic features of 

the various cancers. 

Priority 3: Validate biologic behavior in 

current and future models. 

Rationale 

Each gynecologic cancer has a range of biologic behaviors (e.g., growth, metastasis, 

response to therapy); it will be important to 

determine whether models have similar 

features, especially their responses to 

standard-of-care treatment for individual 

diseases. 

OTHER PRIORITIES 

• Build interaction between investigators 

identifying molecular signatures and 

those developing models. 

• Provide training for young investigators 

in the area of model development. 

BARRIERS 

• Resources for training of investigators 

in cancer models and infrastructure to 

support their interaction with animal 

scientists 

• Infrastructure to provide various in vitro 

and in vivo models to cancer investigators 

• Technology to allow for serial sampling 

of small tumor lesions in in vivo models 

• Limited access to patent-protected 

potential preventive and therapeutic 

agents for testing in available models 

• Resources to develop stable model 

systems that recapitulate human disease. 

For example, mice with a promotor 

and the E6 and E7 genes are not hardy 

and often do not live beyond 1 year, and 

20 to 45 percent of K14-HPV-16 mice 

have problems with bladder obstruction. 

These models often have complications or 

a reduced life span that diminish their 

utility as models. 

• Technology to allow development of 

difficult-to-produce transgenic animal 

strains. Certain models are difficult 

to produce. For example, a PTEN 

heterozygote/DNA mismatch repair 

model is produced in only 1 of 16 

offspring from the relevant parent 

mice. 

RESOURCES 

The National Cancer Institute Mouse Model 

Consortium 

56 Report of the Gynecologic Cancers Progress Review Group 
Health Disparities, Communication, Education, and Quality of Care 

Co-Chairs: Groesbeck Parham, Edward Partridge, and Jane Weeks 

Participants: 

Deborah Bell Diana Jeffery Lari Wenzel 

Mona Fouad Mary Jackson Scroggins Stacey Young-McCaughan 

BACKGROUND: STATE 

OF THE SCIENCE 

As a population, women with cervical 

cancer are characterized by striking 

disparities in mortality and stage at 

diagnosis by race and socioeconomic status. 

To a lesser extent, the same is true of 

women with endometrial cancer. Increased 

research in cervical cancer is needed to 

further define and characterize risk factors 

and the biologic, sociocultural, systems, and 

provider components for these 

discrepancies. 

There are also discrepancies by age and 

geographic region in obtaining Pap smears. 

Older women are less likely to obtain a Pap 

smear, or at least to obtain one regularly, 

than younger women, and women in certain 

areas of the country (such as Appalachia, the 

deep South, and certain areas with large 

Latina populations and subsets of Asian 

populations) are also less likely than the 

general population to obtain Pap smears. 

Research is needed to identify the reasons 

for these discrepancies and to assess 

compliance with follow-up for abnormal 

Pap smears. 

Discrepancies appear to exist even in the 

care provided by specialists to women. 

Some specialists appear to make 

assumptions based on race, education, or 

socioeconomic status about a woman’s 

ability to tolerate or comply with more 

aggressive treatment. Research is needed to 

determine the factors that influence these 

physicians’ decisions. Research is also 

needed on cultural preferences for certain 

communication styles and on interventions for 

improving cultural competency in the health 

professions. In addition, it is not clear what 

sources of information (such as friends or 

family members) patients use to make 

decisions about their treatment. Little 

research has been conducted on follow-up 

care and survivorship in non-white and lowerincome populations. 

Very little is known about whether women 

with gynecologic cancers are receiving 

appropriate quality of care. The evidence 

from other cancers suggests that the quality of 

cancer care is uneven at best. There are 

several reasons why the study of quality of 

gynecologic cancer care could be especially 

informative. First, many women with 

gynecologic cancers are treated by general 

surgeons or general oncologists rather than 

gynecologic oncologists. There is some 

evidence that women with gynecologic 

cancers receive higher-quality care and 

experience better survival under the care of 

specialists, compared with generalists. 

Second, the striking differences in both the 

incidence and outcomes of cervical cancer by 

race suggest that health disparities may be a 

particular problem in the quality of care for 

this disease. One particular clinical 

situation—the treatment of recurrent or 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 57 
refractory ovarian cancer—raises all of the 

issues discussed above. 

RESEARCH PRIORITIES 

Priority 1: Assess the quality of care and 

outcomes of treatment of women with 

gynecologic cancers. 

We propose large observational cohort 

studies of newly and previously diagnosed 

patients with gynecologic cancer, investigating the impact of targeted interventions 

on patient-centered outcomes, dissemination 

of state-of-the-science therapies into 

practice, the influence of modifiable risk 

factors, and disparities in the delivery of 

quality cancer care. We recommend that 

these studies be conducted through the 

newly created, National Cancer Institute 

(NCI)-sponsored Cancer Care Outcomes 

Research and Surveillance Consortium 

(CanCORS), with two modifications. First, 

it is essential that these studies look across 

the disease continuum, from diagnosis to 

treatment to survivorship and end-of-life 

care. Second, these studies must include 

sites with sufficient representation of 

underserved, socioeconomically diverse 

populations to be able to examine health 

disparities in treatment and outcomes. 

Rationale 

Little is known about quality of care and 

outcomes in women with gynecologic 

cancers. Gynecologic cancer survivors 

account for 17 percent of all cancer 

survivors, but only 3 percent of cancer 

research grants go toward research on 

survivorship. The majority of females with 

gynecologic cancer do not receive care from 

gynecologic oncologists; the impact of this 

on quality of care and outcomes is unknown. 

Because gynecologic oncologists provide 

multimodality oncology care, studies of 

quality of care and outcomes for gynecologic 

cancers provide a particularly informative 

setting in which to study specialist versus 

generalist care and volume-outcome 

relationships. 

Priority 2: Assess health disparities in 

cervical cancer incidence and outcomes. 

We propose a multipronged research strategy 

including large database studies, populationbased cohort studies, and in-depth qualitative 

studies, including patient and provider 

interviews. This is necessary to determine the 

relative contribution of risk factors, screening 

(including compliance and follow-up rates), 

treatment (including recommendations, 

patient preferences, and provider expertise), 

and survivorship (including post-treatment 

surveillance) to the observed disparities in 

cervical cancer incidence and outcomes. 

Rationale 

• Marked differences exist in the incidence 

and outcome of cervical cancer that are 

attributable to multiple factors, including 

race, ethnicity, income, age, and 

education. 

• There is a major emphasis among multiple 

cancer institutions, including the NCI, the 

American Cancer Society, and the Centers 

for Disease Control and Prevention, to 

eliminate this disparity over the next 10– 

15 years. 

• To accomplish this goal, it is essential that 

we understand fully and completely the 

influence of the multiple factors 

underlying this disparity, including 

biologic, sociocultural, health care system, 

and provider factors. Without this 

information, it will be essentially 

impossible to design the interventions 

necessary to modify any or all of these 

factors. 

58 Report of the Gynecologic Cancers Progress Review Group 
Priority 3: Study treatment choice and 

outcomes in patients with recurrent or 

refractory ovarian cancer. 

Rationale 

The majority of women diagnosed with 

epithelial ovarian cancer die of their disease, 

yet the effect of second- and third-line 

treatments on survival, quality of life, 

patient satisfaction, and costs is unknown. 

Nonetheless, this treatment has become 

standard care, such that randomized trials of 

chemotherapy versus best supportive care 

are controversial. As a result, there is a need 

to study both the outcomes of this treatment 

and the decision-making process involved in 

choosing a treatment strategy. With careful 

attention to the sociocultural context in 

which physician-patient communication 

occurs, this research will be an informative 

case study about truth-telling, expectations, 

and preferences in advanced cancer. 

BARRIERS 

• The components of optimal-quality care 

have not been defined. 

• Individual investigators do not have 

access to sufficient numbers of cases of 

gynecologic cancers to conduct studies. 

• Health disparities are likely to involve a 

complicated interaction among biologic, 

cultural/individual, systems, and providers 

issues. 

• Race/ethnicity is becoming more difficult 

to define as population migration and 

intermarriage increase. 

• Accrual to large trials in the refractory or 

recurrent ovarian cancer setting may be 

difficult. 

RESOURCES 

• Consortia of investigators collecting 

standardized data in each of the three 

tumor types to provide sufficient numbers 

of patients 

• Quality-of-care indicators 

• Collaboration among investigators with 

expertise in gynecologic oncology, health 

communication, health services research, 

and health psychology 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 59 
Genes and Environment 

Co-Chairs: Paul Goodfellow, Samuel Mok, and Timothy Rebbeck 

Participants: 

Jeff Boyd Lora Hedrick Ellenson Susan L. Scherr 

Kathleen Cho Holly Gallion Joellen Schildkraut 

Louise Chow John McPherson 

Mary B. Daly Marc S. Mendonca 

BACKGROUND: STATE 

OF THE SCIENCE 

Our understanding of the etiology of 

gynecologic malignancies is in its infancy. 

Some of the genetic and environmental 

factors that contribute to risk for developing 

endometrial, cervical, and ovarian cancer 

have been identified. For cervical cancer, 

human papillomavirus (HPV) infection is a 

key environmental factor. For endometrial 

cancer, exposure to unopposed estrogen is a 

major environmental factor. For ovarian 

carcinoma, use of oral contraceptives is 

protective. Some of the germline and 

acquired genetic factors (tumor cell–specific 

events) associated with tumor etiology and 

progression have also been delineated. 

However, it remains largely unknown how 

these genetic and environmental factors 

interact in tumorigenesis. 

Improving our understanding of the 

interaction between genotype and 

environment will afford opportunities for the 

prevention, detection, diagnosis, and 

treatment of gynecologic malignancies. For 

each malignancy there are unique 

opportunities for investigations into the 

causes of cancer. 

ENDOMETRIAL CANCERS 

Endometrial carcinoma is the most common 

gynecologic malignancy in the United 

States: an estimated 36,000 new cases occur 

each year. The overall 5-year survival rate for 

endometrial cancer patients is excellent, due 

in large part to the fact that most tumors are 

detected at an early stage (when the cancers 

are confined to the uterus). Therapies for 

recurrent or persistent endometrial cancer, 

however, are largely ineffective. 

Endometrial cancers are often subclassified as 

type I or type II disease, according to a 

classification system that reflects differences 

in histology, etiology, and behavior. 

Approximately 85 percent of endometrial 

cancer cases are type I, reflecting histology 

arising on a background of abnormal 

endometrial proliferation and carrying an 

excellent prognosis. Type II disease includes 

tumors of the uterine serous and other less 

common histologies that appear to arise from 

the atrophic (non-proliferative) endometrium. 

Exposure to estrogen (both endogenous and 

exogenous) is a potent risk factor for the 

development of type I disease. Estrogenic 

stimulation can result in abnormal endometrial proliferation, or endometrial 

hyperplasia. Nearly 100,000 hysterectomies 

are performed each year in the United States 

because of abnormal endometrial proliferation 

(e.g., atypical endometrial hyperplasia). 

However, it is recognized that in as many as 

75 percent of women who undergo hysterectomy because of a diagnosis of endometrial 

hyperplasia, the disease might not progress to 

60 Report of the Gynecologic Cancers Progress Review Group 
cancer. The mechanism by which 

estrogenic exposure increases the risk for 

endometrial cancer is not well understood, 

nor are the genetic and environmental 

factors that are associated with progression 

to cancer. Different ethnic groups show 

striking differences in the incidence of type I 

(estrogen-promoted) tumors, suggesting that 

there are race-specific unrecognized genetic 

and environmental factors that contribute to 

disease. 

CERVICAL CANCER 

Cervical cancer is the second most common 

cause of cancer-related death worldwide. 

Although the use of the Pap smear has 

reduced the incidence of invasive cervical 

cancer, the test lacks specificity and 

sensitivity. Millions of follow-up 

procedures are performed each year because 

of abnormal Pap smear findings, the vast 

majority of which are benign. 

Human papillomavirus (HPV) infection is 

an early event in cervical carcinogenesis, 

but only a small fraction of women infected 

with HPV go on to develop cancer. 

Smoking and a number of other environmental factors have also been linked to the 

risk for cervical cancer. Genetic factors that 

influence risk for cervical cancer and 

interact with HPV have been identified, but 

the precise nature of these interactions has 

not been determined. Immune response 

genes and, potentially, the TP53 tumor 

suppressor gene somehow interact with 

HPV in cervical tumorigenesis. Why certain 

women with HPV infection go on to develop 

invasive cancers and others do not is 

unknown. 

Several histologically recognizable 

precursors to cervical cancer exist. There 

appears to be a phenotypic progression from 

normal to precancerous intraepithelial 

lesions and to invasive carcinoma. Many 

genetic changes associated with progression 

remain to be determined. 

OVARIAN CANCER 

Ovarian cancer is the leading cause of death 

from gynecologic cancer in the United States. 

The low overall survival rate for patients with 

ovarian cancer is due in large part to the fact 

that most cases are diagnosed at an advanced 

stage. Although the use of chemotherapy has 

improved survival rates, in most patients the 

disease ultimately progresses. 

Ovarian cancer has four distinct histologic 

subtypes: mucinous, serous, endometrioid, 

and clear cell. Each of these appears to be 

associated with a distinct molecular pathway, 

and there may be distinct environmental risk 

factors for each. A variety of nonmalignant 

changes in ovarian carcinoma may represent 

premalignant precursors; these include cystic 

lesions and borderline ovarian tumors, endometriosis, and endosalpingosis. 

Mutations in the BRCA1 gene confer a high 

risk for development of ovarian cancer. Risk 

is also increased among BRCA2 mutation 

carriers. The vast majority of women with 

ovarian cancer, however, do not have an 

obvious familial or genetic risk for the 

disease. 

Several environmental risk factors for ovarian 

cancer are well established, including 

infertility, low parity, late menopause, 

prolonged ovulatory age, and increased 

number of spontaneous abortions. Asbestos 

exposure and the use of talc on the perineum 

has also been linked to an increased risk 

for ovarian cancer. The use of oral 

contraceptives, on the other hand, has a 

protective effect. Different ethnic groups 

show differences in incidence of ovarian 

cancer, pointing to the existence of as yet 

unrecognized genetic and environmental 

factors that contribute to disease. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 61 
OVERARCHING RATIONALE 

To date, studies to assess the effects of 

genetic factors on the risk for developing 

cancer or how the cancer patient’s genotype 

influences tumor progression and response 

to therapy have been conducted “one gene 

at a time.” Although there has been 

considerable progress in identifying and 

characterizing the genes that confer risk for 

certain gynecologic cancers (e.g., BRCA1 

and BRCA2 for ovarian carcinoma and 

MSH2 and MLH1 for endometrial 

carcinoma), these “major” susceptibility 

genes account for only a small fraction of 

gynecologic malignancies. Several lines of 

investigation suggest that inherited genetic 

factors modify the risk for development of 

gynecologic malignancies. Such “modifier 

genes” are likely to work in concert with 

other genetic and environmental factors. 

Common genetic variants could confer an 

increased risk for a specific cancer type, 

might have a general cancer risk effect, or 

could be protective. The effect of any given 

modifier of risk may be relatively small at 

the level of the individual, but because the 

variant forms are common, the effect at the 

population level could be large. Among the 

gynecologic malignancies, it is recognized 

that the risk for cervical carcinoma is 

determined in part by genetic variation in 

the immune response (MHC) genes, which 

somehow mediate patients’ responses to 

HPV infection. Because studies to assess 

the effects of genetic factors have been 

conducted one gene at time, often in 

populations for which environmental risk 

factors are unknown or have not been 

considered, little is known about how genes 

interact with one another and with environmental risk factors. 

Priority 1: Support the development of 

laboratory-based research methods for the 

analysis of tissues and epidemiologic data, 

as well as enhanced collection of tissue 

samples obtained through National Cancer 

Institute (NCI)-designated Cancer Centers, 

Networks, and Cancer Cooperative Groups, 

for development of the following: 

• Tissue banks with linked clinical and 

standardized data on endogenous and 

exogenous risk factors (e.g., reproductive 

history, smoking, hormone use, family 

history, race) 

• Methods for collecting tissues that 

preserve the biomolecules of interest 

(RNA, proteins, DNA) and for working 

with limiting (small-volume) tissue 

sources 

• Banks of “immortalized” RNA for gene 

expression studies, to address the problem 

of limited amounts of RNA for many 

samples and the possibility that amplification may change expression levels 

Rationale 

Although there are a number of recognized 

risk factors for gynecologic cancers, this 

information typically is not linked to the 

research tissue specimen. Additionally, 

current methodologies are inadequate for the 

study of limited tissue resources, and there 

are no robust methods for analysis of precancerous lesions and other very small 

clinical specimens. 

Because information on environmental risk 

factors for the development of cancer is rarely 

obtained as part of routine clinical care, there 

have been few opportunities to determine the 

important exposures and lifestyle factors that 

determine risk. Too often, epidemiologic 

studies have been limited to “looking under 

the lamp post”: in the case of endometrial 

and ovarian cancers, estrogen exposure is a 

known risk factor, and epidemiologic studies 

have focused on factors that are known to 

influence estrogen levels, such as contraceptive use, pregnancy, and smoking. 

Cancer patients, and women in general, may 

62 Report of the Gynecologic Cancers Progress Review Group 
be aware that estrogens might increase the 

risk for developing gynecologic cancers, but 

there is much less known about what foods, 

food additives, chemicals, and pollutants 

add to this risk. Epidemiologic studies are 

usually conducted independent of genetic 

(DNA-based) studies, and it has been 

difficult to merge epidemiologic and genetic 

data to look at how the genome and the 

environment interact. 

A greater understanding of the important 

genetic and environmental factors that 

influence risk for gynecologic malignancies 

holds promise for prevention, detection, and 

treatment of these cancers. The identification of high-risk groups, based on genetic 

profiles, environmental exposures, or combinations of both, could be used to focus 

cancer surveillance efforts and to guide 

chemoprevention and intervention efforts. 

Understanding what genes and pathways 

contribute to tumor development affords 

opportunities for new treatments and prevention strategies. 

Priority 2: Understand the genetic 

influences on environmental factors in the 

development of gynecologic cancers (e.g., 

oral contraceptives in ovarian cancer, HPV 

infection in cervical cancer, and use of 

unopposed estrogen in endometrial cancer) 

through the following: 

• Developing in vivo and in vitro models 

of genotype-environment interactions 

• Identifying and characterizing singlenucleoside polymorphisms (SNPs), in 

candidate genes and across the genome, 

for use in studies of gynecologic cancer 

etiology, progression, and treatment 

response or prognosis 

• Developing novel study design and 

analysis methods that can accommodate 

the complex genomic and genotypeenvironment interaction data required to 

understand these diseases 

Rationale 

Genotype-environment interaction studies 

are in their infancy. The substantial 

characterization of SNPs and the functional 

significance of potential interactions hold 

promise in identifying individuals and populations at risk and in developing strategies for 

prevention and risk reduction. 

In vivo and in vitro models are needed to 

elucidate the biologic mechanism of 

genotype-environment interactions identified 

by epidemiologic approaches and to help 

direct epidemiologic studies that translate 

information from in vivo or in vitro models to 

human populations. Available mouse models 

for gynecologic cancers are inadequate or 

have not been appropriately validated. 

Additional models for these cancers are 

urgently required. Organotypic or new cell 

culture systems in which the cell genotype 

can be manipulated are needed to assess the 

interactions between cellular environment and 

genotype. 

A systematic characterization of SNPs and 

other polymorphic variants in both candidate 

genes and novel variants found by the Human 

Genome Project should include a definition of 

allele frequencies in defined ethnic groups 

(focusing on the major U.S. ethnic groups) 

and the functional significance of SNPs. 

Other high-throughput technologies could be 

used in large-scale molecular epidemiologic 

studies. For example, SNP chips could be 

developed for the evaluation of variants in 

genes of specific metabolic pathways. This 

information is required for the success of 

molecular epidemiologic studies of cancer 

risk, progression, prognosis, and natural 

history. 

Novel study design and statistical analytic 

methods are needed to identify patterns fusing 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 63 
large data sets (i.e., many genotypes and 

epidemiologic risk factors on large numbers of individuals) and evaluate the 

complex interactions of these factors in 

epidemiologic studies. Novel methods for 

data mining, for the purposes of genera

ting hypotheses and distilling large data 

sets to identify relevant factors that can 

be evaluated in traditional hypothesistesting approaches, need to be translated 

into studies of genotype-environment 

interactions. 

Priority 3: Define the environmentally 

related molecular profile (e.g., altered gene 

expression or DNA damage after exposure 

to a carcinogen) of gynecologic tumors to 

identify the following: 

• Heterogeneity in disease that can be 

used to focus studies of genotypeenvironment interactions 

• Homogeneous subtypes of disease for 

improved assessment and clinical 

outcome 

• Patterns of disease progression 

Rationale 

Gene expression profiling studies in breast 

cancers from women with BRCA1 or 

BRCA2 mutations have proven that distinct 

molecular pathways exist in histologically 

indistinguishable tumors. It has become 

evident that there is a need to classify 

tumors with a resolution that is greater than 

that possible using conventional histopathology. By subclassifying gynecologic 

tumors, it should be possible to understand 

the interaction between specific gene or 

environmental effects and tumor behavior. 

Furthermore, elucidation of the genotypic 

progression that underlies phenotypic 

progression will provide opportunities for 

the development of new diagnostics and 

approaches to treatment. 

BARRIERS 

Most early endometrial and cervical 

carcinomas are treated by general-practice 

gynecologists. As a consequence, key tissue 

resources for the study of both genetic and 

environmental factors contributing to cancer 

risk cannot easily be acquired for 

investigation. Methods for fixation of tissues 

that can be used in a routine clinical setting 

are lacking. Furthermore, key epidemiologic 

data are unlikely to be collected in the 

generalist’s practice. 

Available approaches are limited for 

appropriate study design and statistical 

analysis of complex genotype-environment 

interaction data. In addition, there has been 

little support for methodologic research to 

address these issues in gynecologic cancers. 

RESOURCES CURRENTLY 

AVAILABLE 

GENOMIC RESOURCES 

The draft sequence of the Human Genome 

and the wealth of information on 

polymorphism provide opportunities for 

unraveling how the genome and environment 

interact in tumorigenesis. Methods for 

detecting genetic variations among 

individuals, tumor cells, and populations are 

evolving rapidly. Targeted resequencing of 

moderate-to-large–sized genomic intervals of 

interest is likely to become feasible in the 

near future. 

METHODS FOR GENETIC EPIDEMIOLOGY 

STUDIES 

Genetic epidemiology methods are being 

developed that take into consideration both 

genetic and environmental factors. The 

science of data mining for the purposes of 

generating hypotheses (artificial intelligence, 

neural network, and other novel analytic 

approaches) is evolving rapidly. Expression 

64 Report of the Gynecologic Cancers Progress Review Group 
array studies have already distilled large 

data sets to identify relevant factors that can 

be evaluated in traditional hypothesis-testing 

approaches. 

PATIENT SPECIMENS AND MODELS 

FOR INVESTIGATION OF GENOMEENVIRONMENT INTERACTIONS 

Several existing in vivo and in vitro models 

for gynecologic malignancies can be 

exploited to further our understanding of 

how the environment and genome interact 

in tumorigenesis. Mouse HPV models 

(transgenic and cell culture) for cervical 

carcinoma have been devised, as have a 

variety of other cell culture systems. 

Endometrial cancer models for genetic 

factors contributing to disease risk have 

already been developed (phosphatase and 

tension homologue [PTEN] gene and 

DNA mismatch repair knockouts), as 

have hormonal models (estrogenic tumor 

promotion). A wide variety of ovarian 

cancer cell lines have been established and 

extensively characterized. Mouse models of 

ovarian carcinoma are being developed 

through the NCI-funded Mouse Models for 

Cancer Consortium. Systems for culture 

and manipulation of primary ovarian 

epithelium are well established. 

The human tissues available for 

investigation represent a major resource for 

studies to determine how environmental and 

genetic factors interact in tumor initiation 

and progression. Histologically 

recognizable precancerous precursors for 

endometrial and cervical carcinoma are 

accessible for study. These provide unique 

opportunities to define the earliest signatures 

of cancer and the molecular fingerprints that 

the environment leaves on the cell. 

Populations of women with cancers are 

already being assembled by Cancer 

Cooperative Groups such as the NCIsponsored Gynecologic Oncology Group. 

RESOURCES NEEDED 

To maximize the potential for success of the 

recommended research priorities, a number of 

resources should be put in place. In addition 

to the resources specified in Priorities 1 and 2, 

collaborative research groups or consortia are 

needed to allow the substantive interaction of 

genetic and environmental epidemiologists in 

studies of genotype-environment interactions 

in the etiology of gynecologic cancers. 

OPPORTUNITIES 

Several unique research opportunities exist in 

gynecologic malignancies. In cervical and 

endometrial cancer, there are recognized 

potent environmental risk factors, such as 

HPV in cervical cancer and estrogenic 

exposure in endometrial cancer. In both 

cervical and endometrial cancer, there are 

histologically recognizable precancerous 

lesions. These early lesions progress to 

cancer in only a fraction of women. Identifying and characterizing the factors that are 

associated with disease progression will 

provide insights into early events in 

tumorigenesis. With this understanding will 

come opportunities to prevent disease, halt 

progression, and identify those women who 

will benefit most from interventions and those 

for whom minimal intervention is required. 

The ability to distinguish high- and low-risk 

precancerous changes will translate to a 

reduction in costs for continued follow-up and 

care and reduce the burden of “cancer 

concerns” for women who have abnormal Pap 

smears, abnormal uterine bleeding, or other 

potential indications of cancerous or 

precancerous changes. 

Several opportunities also exist for synergy in 

gynecologic cancer research. The histologic 

and biologic similarities in endometrioid 

ovarian and endometrial cancers and in serous 

ovarian and endometrial cancers suggest 

disruption of common pathways. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 65 
Access to precancerous endometrial 

and cervical lesions presents a unique 

opportunity for progress in understanding 

the interaction between genetic and environmental factors in the genesis of solid tumors. 

66 Report of the Gynecologic Cancers Progress Review Group 
Imaging 

Co-Chairs: Hedvig Hricak and Michael Welch 

Participants: 

John D. Chapman Barry B. Goldberg Charles Levenback 

Farrokh Dehdashti Ann Kolker 

Michael A. Friedman Robert Lenkinski 

BACKGROUND: STATE 

OF THE SCIENCE 

Over the last two decades, the imaging 

sciences have made remarkable advances in 

technology for visualizing tissue structure 

and function. Novel imaging paradigms are 

being developed to provide noninvasive 

assessments of tissue (tumor) at cellular or 

molecular levels. Imaging modalities of 

the future are centered on the molecular 

differences between cancer cells and normal 

cells. 

These new approaches will facilitate early 

cancer detection and allow anatomic and 

biologic cancer staging. It will assist in the 

goal to design and implement evidencebased, risk-adjusted, and patient-specific 

therapy. These developments also will 

provide new and exciting opportunities to 

assess signal transduction pathways targeted 

by specific antitumor drugs. For example, 

patients may be selected for a particular 

drug therapy on the basis of imaging prior to 

drug administration, and drug effects could 

be monitored by measuring specific proteinprotein interactions, signal transduction, or 

metabolic pathways. In this way, new endpoints for monitoring drug response could 

be developed. 

Physicians and scientists could benefit from 

quantitative methods for identifying partial 

and complete response. These would serve 

as endpoints to act as a credible surrogate 

Cheryl Marks 

Peggy Olive 

for survival in clinical trials. Another aspect 

of the molecular imaging effort is the ability 

to use reporter constructs to monitor gene 

therapy. For example, it is now possible to 

monitor the distribution, concentration, and 

persistence of viral vectors and the level of 

therapeutic transgene expression by using 

reporter constructs and noninvasive imaging 

techniques. We therefore have an opportunity 

to develop nomograms for specific patientbased individual therapies. 

In imaging, as elsewhere in cancer research, 

animal models of cancer are making it 

possible to perform certain kinds of studies 

that are difficult if not impossible to perform 

in humans. In addition to learning more about 

cancer and development of animal tumor 

models, research with animal models will 

facilitate improvements and developments in 

imaging technology that eventually can be 

applied to clinical cancer care. 

A distinct advantage of noninvasive imaging 

in animal models of cancer is the ability to 

perform repetitive, noninvasive observa

tions of the biologic processes underlying 

cancer growth and development without 

sacrificing the animal. Furthermore, the level 

of resolution with small-animal-imaging 

modalities is now approaching the size of 

individual cells. Imaging in animals can 

also help assess the effectiveness of new 

instruments and therapeutic technologies, 

such as radiation therapy and directed drug 

therapies. Animal models are critical in 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 67 
providing insights that cannot be obtained 

from humans because of practical or ethical 

considerations. Imaging provides a parallel 

modality (in conjunction with biopsy and 

tissue assay) for obtaining information from 

human subjects and animal models, and this 

dual approach can be rigorously applied. 

Based on the current potential in imaging, 

and in synergy with cancer research 

developments, two research priorities for 

dramatic differences in cancer are put 

forward: imaging tumor biology and 

genetics, and developing imaging biomarkers for prediction and assessment of 

treatment response, and even toxicity. 

RESEARCH PRIORITIES 

Priority 1: Imaging of tumor biology and 

genetic signatures. 

Rationale 

Using imaging, it is possible to define a 

signature of cancer cells. Parameters that 

can be quantified include angiogenesis, 

hypoxia, apoptosis, receptors, tumor growth 

kinetics, and pharmacokinetics. Imaging 

can also define the phenotypic heterogeneity 

of tumors. 

Site-specific techniques for cancers of the 

ovary, cervix, and endometrium must be 

developed. These advances will allow the 

early detection and characterization of 

tumors. Surrogate markers that are 

important in the development of treatment 

regimens will be evaluated for proof of 

principle, proof of biologic target, toxicity, 

and tumor response. An example of 

functional imaging of gynecologic cancers 

involves steroid hormone receptors. 

Estrogen and progesterone receptors are 

overexpressed in many endometrial and 

cervical cancers. Positron emission 

tomography (PET) imaging with 18F-labeled 

estradiol has been studied in breast cancer 

and holds great promise in endometrial cancer 

for tumor detection and to guide appropriate 

therapy. PET will permit the determination of 

receptor status of all disease, rather than the 

limited tissue available by biopsy. Similar 

agents to quantify levels of various growth 

factors are under development. 

Priority 2: Imaging biomarkers for predicting and assessing therapeutic response. 

Rationale 

The technologies developed and validated 

under Priority 2 can be used in planning 

individual patient treatment protocols as well 

as in clinical trials involving new drugs. The 

latter will involve both agents aimed at the 

biologic target as well as surrogate markers. 

These technologies will allow the determination of endpoints in a very short time in all 

areas discussed. Specifically, imaging will 

assist in the following: 

• Design of individual treatment 

• Early assessment of treatment efficacy 

• Implementation of surrogate endpoints in 

clinical trials 

• Drug development and response 

BARRIERS 

Modern molecular imaging involves 

interdisciplinary science. It depends on 

building and sustaining a strong research 

infrastructure. It should promote and practice 

science without the traditional specialtydriven walls of medicine. A lack of trained 

imaging scientists in key scientific areas (e.g., 

physician scientists, cellular and molecular 

biologists, chemists, physicists, mathematicians, and engineers) is a major barrier to the 

widespread application of modern molecular 

imaging technology. 

68 Report of the Gynecologic Cancers Progress Review Group 
Imaging discoveries and developments are 

driven by both technology and biology. 

Technology of modern imaging (nuclear 

magnetic resonance, ultrasound, and optical) 

is rapidly developing. Cancer-specific 

contrast media are emerging as well. 

Understanding the potentials and limitations 

of each technology is essential for their 

proper utilization. Furthermore, the lack of 

standardization in the evaluation of modern 

imaging techniques is yet another barrier. 

All new techniques must be validated and 

standardized prior to their widespread 

implementation and dissemination. 

RESOURCES 

An infrastructure including facilities, 

equipment, and personnel in imaging 

science is needed. We recommend the 

following: 

• Establish imaging centers of excellence 

for laboratory and clinical research. 

• Ensure supplemental funding for 

translational research in imaging. 

• Train new generations of imaging 

scientists knowledgeable in the biology 

and technology of imaging. 

• Bioinformatics—Develop and support 

research-oriented PACS (patient archiving 

and communication system) for image 

data management, analysis, and 

application of new computer-driven 

technical advances such as image fusion 

to allow “biological tumor volume,” 

three-dimensional assessment of tumor 

extent, and automatic tumor volume 

measurement for monitoring treatment 

response. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 69 
Tumor Biology, Hormone Receptors, Epithelial-Stromal Interactions, 

and Early Activation 

Co-Chairs: Kimberly Leslie and Karl Podratz 

Participants: 

William T. Beck Nita Maihle Barbara Vanderhyden 

Mary (Nora) Disis Franco Muggia John Wiktorowicz 

Patricia Goldman Kevin G. Osteen Aaron Wolfson 

Thomas C. Hamilton Martha C. Romans Richard J. Zaino 

Silvia Curtis Hewitt Neeraja Sathyamoorthy 

BACKGROUND: STATE 

OF THE SCIENCE 

The endometrium, ovary, and cervix are 

hormone-responsive sites within the female 

reproductive tract. The link between 

estrogen-induced proliferation and 

progesterone-induced differentiation is 

well established in the malignant and nonmalignant endometrium. Newer findings 

relating to the protective effects of oral 

contraceptives on the risk of developing 

ovarian cancer suggest that progesterone 

may inhibit carcinogenesis, and provocative 

but preliminary studies in cervical cancer 

support a role for hormones in the regulation 

of human papillomavirus (HPV). Although 

hormonal regulation is initiated via ligand 

binding to specific receptors that have been 

appropriately assembled, it is the subsequent 

interaction with coregulators and the 

transcriptional machinery that results in the 

desired corresponding hormone effect. 

The microenvironment within which 

malignant transformation occurs is complex 

and poorly understood. When significant 

alterations occur, a preneoplastic lesion or 

malignant transformation results. Our 

understanding of the etiologic processes 

resulting in transformation within all 

gynecologic tissue sites is limited, and 

studies to address this scarcity are urgently 

needed. 

Although the majority of endometrial cancers 

are hormone dependent, some become 

resistant, and our current knowledge regarding their uncontrolled growth, invasion, 

and metastasis is incomplete. Evidence 

from breast cancer research suggests that 

alterations in hormone receptor isoform 

expression, assembly, modulation, and/or 

degradation may be predisposing etiologic 

factors. Furthermore, the altered hormonal 

milieu appears to activate growth factor 

pathways. 

In contrast, hormone-independent tumors 

appear to harbor constitutively activated 

growth factor pathways. Our knowledge of 

the molecular interactions, or “cross-talk,” 

among hormones, specific growth factors, 

hormone and/or growth factor receptors, 

coregulators, and other modulators of the 

physiologic processes requires expansion. 

The complexity of the interactions in both 

hormone-dependent and -independent tumors 

is magnified by the important, but poorly 

understood, interdependence of the stroma 

and the epithelium. The origin of the 

abnormal over- or under-expression of 

hormones and/or growth factor in the 

microenvironment is presumed to be the 

70 Report of the Gynecologic Cancers Progress Review Group 
result of epithelial-stromal interactions. For 

example, in the endometrium, abnormalities 

in the surrounding stroma are associated 

with endometriosis and possibly with early 

events in epithelial carcinogenesis, but this 

is an area of tumor biology that is essentially 

unexplored. 

Challenges and questions include the 

following: 

• What are the etiologic events that result 

in the transformation of hormonedependent tumors? 

• What are the identifiable molecular 

events in hormone-independent tumors? 

• What are the molecular mechanisms 

facilitating the interactions and synergy 

between hormones and growth factors 

and their corresponding receptors? 

• What are the etiologic and maintenance 

factors that are localized to the various 

histologic compartments and their 

specific roles in carcinogenesis in the 

female reproductive tract? 

• What are the alterations in the hormone 

receptors, growth factors and their 

respective receptors, and epithelialstromal interactions as a function of 

aging, ethnicity, body mass index, and 

tissue variables, as well as biologic 

processes including puberty, pregnancy, 

and menopause and exposures to 

commonly used pharmacologic agents, 

including oral contraceptives, hormone 

replacement therapy (HRT), and 

selective estrogen receptor modulators 

(SERMs)? 

RESEARCH PRIORITIES 

Priority 1: Elucidate the role of stromalepithelial interactions in transformation, 

tumor growth, and invasion. 

• Evaluate the activity of enzymes such as 

aromatases, 17-beta-HSD (hydroxysteriod 

dehydrogenase), and sulfatases that 

potentially influence the hormone levels 

in the microenvironment. 

• Address the stromal versus epithelial 

regulatory influence on growth, invasion, 

and metastasis by growth factors including 

members of the epidermal growth factor, 

tumor growth factor-alpha, and insulin-like 

growth factor families as well as angiogenic factors and proteases. 

• Evaluate the effects of selective hormone 

modulators (selective estrogen receptor 

modulators, selective progesterone receptor 

modulators [SPRMs], etc.), as well as 

hormones used for oral contraception or 

HRT, on the epithelium as well as the 

stroma. 

Rationale 

The interactions between the hormonally responsive stroma and epithelium in the uterus, 

ovary, and cervix are not well understood. 

The stroma may be a major target of hormones and may in turn affect the epithelium. 

Previous studies have examined tumors 

and/or cells in isolation without considering 

the microenvironment. New data suggest 

that an abnormal microenvironment may predispose to transformation, uncontrolled 

growth, and invasion. Information in this 

area will illuminate the etiology of reproductive tumors and will ultimately contribute 

to novel chemoprevention and early detection 

strategies. 

Aromatase inhibitors, growth factors, 

proteases, and angiogenic factors must all be 

examined in the context of stromal-epithelial 

interactions. Questions to be answered 

include the following: 

• Are there ethnic differences in 

expression? 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 71 
• What are the differences between normal 

and malignant tissue expression? 

• What are the effects of aging? 

Priority 2: Understand hormone receptor 

expression, assembly, degradation, and 

modulation. 

• Evaluate the expression of hormone 

receptors and their isoforms in malignant 

and non-malignant reproductive tissues, 

including tumor subtypes such as 

endometrioid, papillary serous, and clear 

cell. 

• Address hormone receptor induction 

and down-regulation by multiple 

mechanisms, including transcriptional 

regulation, translation, and posttranslational modification and 

degradation. 

• Determine the effects of hormone 

receptor co-modulators on receptor 

function. 

• Evaluate the genes induced by hormones 

through their receptors and receptor 

isoforms. 

• Investigate receptor complex assembly 

on DNA and chromatin remodeling in 

response to hormone agonists and 

antagonists. 

Rationale 

Tumors of the female reproductive tract are 

hormonally regulated, and steroid hormones 

act through receptors. Despite much research in breast cancer, little is known about 

hormone receptor expression, assembly, 

degradation, and modulation in response to 

co-activators, co-repressors, or hormone 

agonists and antagonists. The understanding 

of receptor isoforms is key to this priority. 

Priority 3: Improve understanding of the 

interactions among hormones, hormone 

receptors, growth factors, and growth factor 

receptors. 

• Integrate multiple pathways to cell 

growth: determine the points of cross-talk 

between steroid hormones and their 

receptors and other pathways to cell 

growth, including growth factors and 

growth factor receptors. 

• Determine links between hormones and 

factors that promote tissue invasion by 

stimulating angiogenesis and cancer cell 

morphogenesis. 

• Investigate the link between constitutive 

activation of growth factors and the 

development of hormone-independent 

tumor growth. 

• Study the clinical as well as the basic 

science aspects of new therapeutic agents 

to block growth factor receptors on cell 

growth and tumor hormone dependence. 

Rationale 

Multiple pathways drive tumor cell growth. 

Hormone-dependent tumors rely on hormones 

to drive growth, which in turn activate growth 

factor pathways. Hormone-independent 

tumors may be characterized by the 

constitutive activation of one or more 

components of a growth factor pathway, such 

as her-2-neu or epidermal growth factor 

receptors. New data suggest that the loss of 

hormone receptors and growth factor 

activation may be linked. Cross-talk between 

these pathways should be studied to provide a 

more complete understanding of cancer cell 

growth. In addition, the availability of new 

molecules to block growth factor pathways 

may have relevance for the management of 

gynecologic tumors. This area of research 

may lead to the use of molecules such as 

72 Report of the Gynecologic Cancers Progress Review Group 
tyrosine kinase inhibitors to restore hormone 

dependence and facilitate treatment. 

BARRIERS 

• Tissue resources: Lack of tissue for use 

in tumor biology studies, specifically 

normal and adequate tumor specimens. 

With regard to the latter, the availability 

of the less common tumor types (e.g., 

clear cell, serous, tamoxifen-associated) 

is critical. 

• Informed consent: The increasing 

difficulty in securing informed consent 

resulting from extramural mandates is an 

ever-increasing challenge in accessing 

specimens for biomedical research. 

• Challenges regarding patient accrual to 

clinical/translational trials: Only a small 

proportion of women with gynecologic 

malignancies participates in clinical 

trials. This may be due to resistance on 

the part of the patient or the referring 

physician or to the lack of dissemination 

of information on the availability of 

experimental therapies. 

• There are limitations pertaining to the 

availability of reliable tools for assaying 

receptor isoforms, phosphorylation sites, 

etc. 

• Challenges regarding technology and 

methods for the investigation of the 

epithelial and stromal interactions and 

the validation of these investigation 

tools. 

• Appropriate reagents, and protocols for 

their application, to identify hormone 

receptor isoforms and other molecules of 

interest should be rigorously tested and 

standardized for widespread research and 

clinical use. For example, the currently 

available antibodies purported to 

recognize receptor isoforms may be 

nonspecific. 

• The rapid institution of exploratory 

clinical trials in gynecologic malignancy 

is hampered by the lack of multi-center 

consortiums that (1) have an interest 

in novel therapies and translational 

investigations and (2) can act quickly 

to institute studies. 

RESOURCES 

• Advocates are a key resource to help 

educate the patient community about the 

importance of entering clinical trials and 

donating surgical tissue for future 

research. They may also help to increase 

acceptance of new methods of treatment 

in clinical trials, such as the need for serial 

biopsies. 

• Multi-center groups, such as the Gynecologic Oncology Group (GOG), are 

important resources that allow clinical 

trials to be carried out in patients with 

relatively infrequent tumor types. In 

addition, new consortium groups should 

be established to promote multi-center 

trials using novel or exploratory therapies 

that do not fall within the purview of 

GOG. 

• Existing tissue collection facilities 

within the GOG and the National 

Cancer Institute are useful but should 

be expanded. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 73 
Angiogenesis, Metastasis, and Growth Signaling 

Co-Chairs: Michael J. Birrer, David M. Gershenson, and M. Sharon Stack 

Participants: 

Jeffrey Arbeit Peggy A. Crowley-Nowick Sundaram Ramakrishnan 

Carolyn M. Ballard Yi-Shin Kuo 

Robert Bast Peter J. O’Dwyer 

ANGIOGENESIS 

BACKGROUND 

The process of angiogenesis is critical to 

tumor formation and metastatic spread. In 

addition, angiogenic growth factors 

contribute to the unique biology of 

gynecologic cancers (e.g. ascites 

development). New blood vessel formation 

is required as the primary tumor grows and 

spreads. The molecular definition of 

angiogenesis is evolving, with new targets 

identified and agents characterized that can 

interact with them. Unfortunately, the 

heterogeneity of vessels, the complexity of 

the process, and all of the targets have yet to 

be defined. 

ANGIOGENESIS RESEARCH PRIORITIES 

Priority 1: Develop better in vivo and in 

vitro models that will demonstrate all 

elements of angiogenesis in use in 

preclinical drug development. 

Relevant Questions 

• Which angiogenic regulators are 

important in gynecologic tumors? 

• Can in vivo and in vitro models be used 

to prioritize known anti-angiogenic 

compounds for clinical trials? 

Branimir I. Sikic 

T. C. Wu 

Rationale 

Angiogenesis is a critical process in the 

oncogenesis of gynecologic cancers. It 

provides a unique target for agents that would 

be non-cross-resistant with traditional drugs. 

The development, validation, and widespread 

availability of models in which to test these 

agents would facilitate drug development and 

prioritization. 

Priority 2: Characterize vessel biology and 

delineate the molecular basis for vessel 

heterogeneity. Identify and characterize 

novel angiogenesis genes. 

Relevant Questions 

• What is the normal state of vessel biology 

and how is it hormonally regulated? 

• What dictates vessel heterogeneity and 

regional differences in vessels? What is 

the functional/biologic significance of 

these differences? 

• What is the effect of the microenvironment on vessel growth and development? 

• Can genomics/proteomics approaches be 

used to identify and characterize novel 

angiogenesis genes and delineate the 

molecular basis for vessel heterogeneity? 

74 Report of the Gynecologic Cancers Progress Review Group 
Rationale 

The basic biology of tumor versus that of 

normal blood vessels remains unknown. To 

effectively identify and use new antiangiogenesis agents, we need to better 

understand the overall biology of angiogenesis. Emerging data have demonstrated 

a surprising amount of vessel heterogeneity. 

This finding has dramatic implications for 

the role of blood vessels in tumor formation 

and the development anti-angiogenesis 

agents. Further, an understanding of this 

heterogeneity will be important for 

predicting response. 

Priority 3: Develop better methodologies 

for the clinical analysis and prioritization of 

anti-angiogenesis agents. 

Relevant Questions 

• How can we encourage the use of 

angiogenesis inhibitors in phase I trials 

of gynecologic cancers? 

• Can we take advantage of new imaging 

technologies to assess endpoints? 

Rationale 

Angiogenesis provides a unique target for 

agents that would be non-cross-resistant 

with traditional drugs. However, among 

the major problems in the field of antiangiogenesis are the large numbers of 

emerging agents, the small numbers of 

patients, and the limited ways in which 

these can be prioritized. More extensive 

preclinical testing and better biologic 

endpoints in clinical trials would assist in 

prioritizing these agents. 

RESOURCES 

• Appropriate animal models to explore 

the basic science of angiogenesis and to 

screen for agents that inhibit this process 

• Carefully obtained and processed normal 

and malignant tissues to characterize the 

process of angiogenesis 

• Validated biomarkers for each molecular 

element involved within the process of 

angiogenesis 

BARRIERS 

• A lack of understanding of the basic 

biology of anti-angiogenesis 

• Limited resources to make clinical-grade 

materials 

• Minimal preclinical models and clinical 

trials with relevant biologic endpoints to 

prioritize new agents 

METASTASIS 

BACKGROUND 

The subject of this Progress Review Group is 

three very distinct organ sites, each with 

unique aspects. This discussion focuses 

primarily on general problems in metastasis 

research in gynecologic malignancies. The 

vast majority of patient mortality is attributed 

to metastatic disease. Therefore, a more 

detailed understanding of the factors that 

initiate, promote, or ultimately prevent 

metastasis will have an immediate and 

significant clinical impact. 

A major goal of metastasis research is to 

elucidate key factors of tumor biology and 

their relationship to metastatic progression 

and dissemination. This approach may 

ultimately yield new treatments for metastatic 

disease. Cancer of the endometrium and of 

the cervix each account for 6 percent of all 

cancers in women in the United States. Most 

cervical cancers are associated with HPV 

infection, and the majority (> 90 percent) can 

be detected through use of the Pap smear. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 75 
In contrast, ovarian carcinoma, the fifth 

most frequent cause of cancer death in 

women, is so resistant to early detection that 

the majority of patients are diagnosed with 

advanced disease. This results in a mortality 

rate that is approximately 65 percent of the 

incidence rate. 

Mechanisms of metastasis are likely to differ 

in ovarian cancer, in which metastatic 

dissemination is commonly via local 

shedding into the peritoneum, followed by 

peritoneal implantation, invasion, and 

growth. 

METASTASIS RESEARCH PRIORITIES 

Priority 1: Develop and validate model 

systems to promote understanding of 

metastatic disease. Develop, validate, and 

widely disseminate cell culture, co-culture, 

and organ culture models as well as 

transgenic and knock-out animal models. 

Relevant Questions 

• Can we develop and validate wholeanimal model systems that more 

accurately mimic tumor biology? Does 

tumor biology differ in the context of the 

affected tissue? To answer these 

questions requires orthotopic models. 

• Can the appropriate and specific 

promoters be identified for use in a 

transgenic approach to induce organspecific expression (or lack thereof) of 

specific genes thought to be relevant in 

metastasis? 

• Can these models be exploited for 

testing the efficacy of novel therapeutic 

agents? 

• Can cell lines be generated from normal, 

premalignant, and cancerous gynecologic tumors and widely disseminated 

for study in multiple laboratories? 

• What are the appropriate organ-specific 

co-culture or organ culture systems? How 

can these be validated? 

Rationale 

The vast majority of patient mortality from 

gynecologic cancer is attributable to 

metastatic dissemination, yet we currently 

possess a limited understanding of the 

molecular, cellular, tissue, and organ level 

of the factors that initiate, promote, and 

ultimately prevent metastasis. This 

knowledge is essential for the develop

ment of novel therapeutic approaches for 

treatment and prevention of metastatic 

disease. Although early detection of gynecologic cancer is a priority area, in the 

absence of effective early detection strategies, effective treatments for metastatic 

disease will ultimately impact favorably on 

patient mortality. 

Priority 2: Characterize the basic biology of 

normal, cancerous, and metastatic tissues. 

Relevant Questions 

• What biochemical and molecular 

interactions are important for normal 

tissue development during organogenesis, 

morphogenesis, and differentiation? What 

genes control this process and how does 

transcriptional/translational activation of 

these genes differ in the primary tumor 

and metastases? Relevant animal models 

that accurately recapitulate the disease 

process are essential here. 

• What is the basic cell and molecular 

biology of the normal organ, with 

particular emphasis on events that induce 

or control neoplastic progression to the 

malignant and ultimately metastatic 

phenotype? Is there a defined precursor 

lesion? Relevant animal models that 

accurately recapitulate the disease process 

are essential here. 

76 Report of the Gynecologic Cancers Progress Review Group 
• Do the molecules that participate in 

epithelial-stromal interactions vary in the 

normal organ relative to the primary 

tumor or metastatic lesion? Does this 

cause differential activation of specific 

and identifiable signaling pathways? 

• How can emerging technologies in 

genomics and proteomics be best applied 

to the problem of metastatic disease? 

Are the appropriate normal, primary, 

and metastatic tissue specimens 

widely available? Is there sufficient 

bioinformatics support? 

Rationale 

In gynecologic cancer our understanding of 

tumor biology is limited in large measure 

by a lack of detailed information about 

normal tissue development, organogenesis, 

morphogenesis, and differentiation. This in 

turn hampers efforts to identify aspects of 

aberrant patterns of growth in tumors and 

metastatic lesions. Evaluation of cell 

signaling and loss of growth control, normal 

epithelial-stromal interactions, develop

ment of cancerous lesions (i.e., whether 

there is a defined precursor), and genomics/ 

proteomics-based analysis of normal, premalignant, and malignant cells should be 

encouraged. 

Priority 3: Identify and characterize 

molecular targets unique to metastatic cells. 

Relevant Questions 

• What specific molecules or groups of 

molecules control localized invasion, 

migration, and metastasis? Relevant 

animal and culture models are essential 

here. 

• How do cell-matrix and cell-cell 

(epithelial-epithelial, epithelial-stromal, 

or epithelialendothelial) interactions 

contribute to metastasis? What are the 

relevant signaling pathways activated by 

these interactions and how do they differ 

from those in normal cells? 

• How are metastatic cells disseminated? 

Addressing this question requires 

consideration of intravasation as well as 

lymph node metastasis. Ovarian cancer is 

unique here in that dissemination takes 

place predominantly via direct extension 

into the peritoneal cavity, indicating a 

distinct set of problems to address. 

• Are there specific changes in cytoskeletal 

architecture that enhance the “flexibility” 

or “deformability” of tumor cells relative 

to normal epithelium? This question 

requires investigators with experience in 

cellular biophysics to apply their expertise 

to gynecologic malignancies. 

• How does proteolytic activity contribute 

to migration and invasion? What are the 

target substrates in the stroma and on the 

cell surface? 

Rationale 

Metastatic cells represent a distinct subpopulation of tumor cells with the ability to 

escape the primary tumor and establish a 

secondary lesion. The cellular properties that 

distinguish metastatically competent cells 

from other cells in the tumor must be 

identified. These attributes may represent 

novel targets for therapeutic intervention. It 

should be re-emphasized that the majority of 

deaths from gynecological malignancies are 

directly attributable to metastatic disease, 

such that identification of molecular targets 

unique to metastatic cells may have 

immediate therapeutic impact. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 77 
Cancer 

Type 

No. of 

Funded 

Projects 

No. of 

Metastasis 

Projectsa 

Cervical 455 7b 

Endometrial 207 3c 

Ovarian 575 16d 

BARRIERS 

Based on 1999 statistics from the National 

Cancer Institute (NCI) and the American 

Cancer Society, more than 75,000 gynecologic cancers were diagnosed in 1999 and 

over 25,000 women died from these 

diseases. The majority of these deaths 

are directly attributable to metastatic 

disease. However, a significant barrier 

to progress in this area becomes apparent 

upon analysis of the NCI Cancer Research 

Portfolio (researchportfolio.cancer.gov). 

These data demonstrate that less than 3 

percent of the total funding allocated to 

the study of gynecologic cancers is used 

directly for metastasis research. 

a

Obtained from a search combining the terms cancer type

and metastasis b

Two R01 and five P30 Center Grants 

c

Three P30 grants

d

Six R01, six P30, and two Z01 grants 

RESOURCES 

• A review of the Glossary of Select NCI 

Initiatives indicates that funding 

mechanisms are in place to support 

animal model development and 

genomics/proteomics. A pool of these 

funds should be earmarked specifically 

for development of relevant metastasis 

models for gynecologic cancers, and 

investigators should be encouraged to 

apply to these mechanisms for studies of 

gynecologic malignancies. 

• There are no apparent funding mechanisms specifically for metastasis 

research. The NCI is strongly encouraged to supply targeted funding 

for metastasis research in general and for 

gynecologic malignancies specifically. 

• New funding mechanisms should be 

added to promote cross-disciplinary 

research and to attract new investigators 

in other important areas of biology (e.g., 

developmental biology/organogenesis, 

cellular biophysics) to focus on these 

gynecologic cancer models. In particular, 

an increased understanding of the cell, 

molecular, and developmental biology 

of the normal organ is a necessary 

prerequisite for comparative studies of 

malignant and metastatic tissues. 

GROWTH SIGNALING 

BACKGROUND 

Three decades of molecular biologic 

discovery culminating in the recent genomic 

revolution has identified a complex network 

of signal transduction pathways, which are 

critical for the growth, differentiation, and 

survival of normal and malignant cells. These 

pathways involve a myriad of proteins, 

including growth factor receptors and their 

ligands, intracellular signal transduction 

molecules such as kinases and phosphatases, 

and downstream transcription factors. These 

signaling pathways are most certainly tissue 

and tumor specific and are modulated by both 

micro- and macro-environmental influences 

such as the stroma and treatment modalities. 

This complex, dynamic signaling network 

will provide clues to the etiologies of cancer, 

sensitivity to treatment modalities, and 

malignant aggressiveness. Further, understanding these pathways will provide an 

outstanding opportunity for the identification 

of novel target molecules, which can be then 

utilized for the development of unique 

therapeutic agents. 

Unfortunately, signaling pathways in 

gynecologic cancers and their normal 

78 Report of the Gynecologic Cancers Progress Review Group 
tissue counterpart remain essentially 

uncharacterized. Many pathways that have 

been well characterized in other tumors have 

not been investigated in gynecologic 

cancers. Further, the potential for unique 

signaling pathways within gynecologic 

cancers remains a real possibility. 

GROWTH SIGNALING PRIORITIES 

Priority 1: Define signaling pathways that 

regulate growth and survival in normal and 

malignant gynecologic tissues and validate 

them in appropriate animal models. 

Rationale 

The signal transduction pathways in 

gynecologic cancers remain essentially 

unknown. Their elucidation and 

characterization will provide the following: 

• Outstanding targets for small molecules, 

which can modulate their activity. 

These agents will be ideal potential 

chemotherapeutic and chemopreventive 

drugs. 

• Provide important information 

concerning the etiology of these cancers. 

Priority 2: Redesign each early clinical 

trial to efficiently assess a large number of 

small molecules in a limited pool of patients. 

Rationale 

Many small molecules that affect signal 

transduction pathways will become available 

in the near future. It is reasonable to 

predict that these new agents will rapidly 

overwhelm the present preclinical and 

clinical trial design. To assess their clinical 

efficacy, a streamlined trial design will be 

needed to rapidly and efficiently determine 

the activity of these agents. 

Priority 3: Identify the molecular signatures 

of specific signaling pathways that have been 

shown to be dysregulated in gynecologic 

cancer. 

Rationale 

To determine the precise elements of a 

signaling pathway, laboratory-based 

approaches will be required to manipulate a 

single pathway in a controlled fashion and 

examine its downstream effects by use of 

genomic analysis. This cataloguing of 

pathways in different gynecologic tissues will 

be a powerful database that will serve to 

further identify potential molecular targets, 

create potential screening assays for drug 

development, and help interpret genomic 

analyses of gynecologic tissues. 

BARRIERS 

• Scarcity of data concerning the signaling 

networks within gynecologic cancers 

• A complete lack of knowledge of 

signaling pathways in normal gynecologic tissues 

• Inadequate supplies of appropriate tissue 

specimens 

• Lack of smooth and efficient transfer of 

knowledge and reagents between industry 

and academics 

• Lack of appropriate in vitro and in vivo 

(animal) models 

RESOURCES 

• Tissue banks utilizing appropriate tissue 

processing. There is a need for carefully 

selected, removed, and frozen specimens, 

which can be used for phosphoprotein, 

enzymatic, and protein analysis. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 79 
• Appropriate in vivo and in vitro models • Redesigned clinical trials would allow 

and small molecule inhibitors molecules in small numbers of patients 

for screening and validation of pathways for the testing of large numbers of small 

• Strong and close industrial-academic with biologic endpoints. 

collaborations will be needed to • Well-tested, validated, and broadly efficiently develop effective drugs for applicable genomic techniques. newly identified molecular targets. 

80 Report of the Gynecologic Cancers Progress Review Group 
Early Detection, Screening, and Prevention 

Co-Chairs: Andrew Berchuck and Beth Y. Karlan 

Participants: 

Ruedi Aebersold Robyn Kravit Mark Schiffman 

Garnet L. Anderson Susan Lowell-Butler Ellen Sheets 

Jane Fountain Douglas R. Lowy Steven Skates 

Judy Garber Trish May Diane Solomon 

Diana Patricia Garcia David Mutch Joan Walker 

BACKGROUND 

Both screening/early detection and 

prevention approaches were successfully 

employed to reduce cancer mortality in the 

20th century. Most cancers for which 

screening has an impact on mortality (e.g., 

cervical and colorectal cancers) are 

relatively common and have a well-defined 

preinvasive lesion, and screening efforts 

focus on detection and eradication of these 

precursors. Easy accessibility of the target 

organ is another characteristic of cancers 

(e.g., cervical and breast cancers) in which 

screening and early detection programs 

have been successful, as this facilitates 

identification of preinvasive and early 

invasive changes. Pap smear screening 

has dramatically reduced cervical cancer 

mortality and serves as a paradigm for the 

potential efficacy of this approach. 

The enormous potential impact of 

preventive approaches in controlling 

cancer mortality also has been clearly 

demonstrated. Elimination of nitrates as 

food preservatives with the introduction of 

refrigeration in this country led to a large 

decrease in the incidence of stomach cancer. 

Likewise, the striking relationship between 

tobacco use and lung, head, and neck 

cancers is now well known. In these cancers 

prevention can be accomplished by 

avoidance of identifiable exogenous 

carcinogens. 

The potential for development or improvement of screening/early detection or prevention strategies for gynecologic cancers is 

discussed in the following sections. 

OVARIAN CANCER 

In 2001, about 23,400 new cases of ovarian 

cancer will be diagnosed in the United States, 

and about 13,900 of affected women will die 

of their disease. Some ovarian cancers are 

detected at an early stage, when cures are 

easily achieved, but too often these cancers do 

not produce alarming symptoms while still 

confined to the ovaries, and extensive 

intraperitoneal metastases are found at 

diagnosis. Although debulking surgery and 

platin-paclitaxel chemotherapy substantially 

increase median survival, few women with 

advanced disease are cured. Active new 

cytotoxic agents may further extend survival, 

but treatment of these cancers at the point 

when there is an enormous tumor burden may 

not be the most effective approach to 

decreasing ovarian cancer mortality. 

Screening and early detection represents a 

promising strategy for decreasing ovarian 

cancer mortality, because 90 percent of 

ovarian cancers confined to the ovary can be 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 81 
cured. Significant obstacles to early 

detection exist, however. The ovaries are 

small, relatively inaccessible organs that lie 

in the peritoneal cavity, and most masses 

that arise in the ovaries are not malignant or 

even premalignant. The preinvasive lesion 

that precedes the development of ovarian 

cancer remains unknown. Transvaginal 

ultrasound and the CA-125 blood test have 

been explored as potential tests for the early 

detection of ovarian cancer, but both suffer 

from less than acceptable sensitivity and 

specificity. For example, most ovarian 

masses detected by ultrasound are not 

malignant, and about 3 percent of healthy 

postmenopausal women have an elevated 

CA-125 level. Although the ability of these 

tests to decrease ovarian cancer mortality is 

under evaluation in large population-based 

studies, existing data suggest that further 

refinement will be needed to create a costeffective screening procedure. Because the 

disease is uncommon, a cost-effective 

program will require either a very accurate 

screening method or a method of triaging 

women by risk or both. Further research 

efforts on both aspects are needed. In 

particular, gene arrays and other techniques 

that allow global analyses of expression 

patterns have the potential to identify 

markers of stage I disease that could greatly 

facilitate early detection. A Gail-type model 

for ovarian cancer could be useful for both 

efficient trial designs and implementation of 

screening programs. 

In view of the formidable obstacles to 

treatment and early detection, prevention 

of ovarian cancer should be seriously 

considered as a means of decreasing 

mortality. Epidemiologic studies have 

shown that oral contraceptive use and 

pregnancy are associated with marked 

decreases in ovarian cancer incidence. Use 

of the pill for 5 years or having 3 children 

reduces the risk of ovarian cancer by about 

50 percent. This may be attributable to 

reduction of the numbers of lifetime 

ovulatory cycles, but there is also evidence 

that the progestagenic milieu of oral 

contraceptives and pregnancy may have a 

direct preventive effect by inducing apoptosis 

in the ovarian epithelium. This suggests 

the potential for development of chemoprevention strategies that could have a 

significant impact on ovarian cancer 

mortality. In addition, tubal ligation and 

hysterectomy significantly reduce risk, 

perhaps due to interruption of access of 

potential carcinogens via the genital tract, and 

this also presents an opportunity for risk 

reduction. Again, the low ovarian cancer 

incidence rates make direct assessment of 

prevention strategies difficult and costly. 

The lack of surrogate endpoints and wellcharacterized animal models represent 

significant barriers for intermediate testing 

of these approaches. 

ENDOMETRIAL CANCER 

About 35,000 new cases of endometrial 

cancer are diagnosed annually in the United 

States, and most are confined to the uterus 

and can be cured surgically. About 5 percent 

of endometrial cancers have a hereditary basis 

and occur due to inherited mutations in one of 

the DNA mismatch repair genes in the context 

of hereditary non-polyposis colorectal cancer 

(HNPCC) syndrome. Sporadic endometrial 

cancers have been characterized as type I or 

type II based on etiologic, pathologic, and, 

more recently, molecular features. Type I 

cancers are more frequent, particularly in 

whites, and arise due to unopposed estrogenic 

stimulation of the endometrium. Endometrial 

hyperplasia has been shown to represent a 

precursor of type I endometrial cancers, and 

these premalignant lesions can be targeted for 

screening (tissue biopsy) and prevention 

(progestin) strategies. The source of unopposed estrogen in type I cases may be 

endogenous (obesity, nulliparity) or 

exogenous (hormone replacement, 

tamoxifen). These cancers usually are 

82 Report of the Gynecologic Cancers Progress Review Group 
well-differentiated, diploid, endometrioid, 

early-stage lesions that frequently exhibit 

mutations in the phosphatase and tension 

homologue (PTEN) tumor suppressor gene. 

Type II cancers are not associated with 

unopposed estrogen and usually are poorly 

differentiated, aneuploid, and nonendometrioid (serous, clear cell); have 

alterations in genes associated with virulent 

behavior (p53, HER-2/neu); and often 

present at an advanced stage. African 

Americans more often have type II cancers, 

and their survival is significantly worse than 

that of whites. 

Most endometrial cancers occur in 

postmenopausal women and are heralded by 

vaginal bleeding, which leads to early 

diagnosis by endometrial biopsy. It has 

been demonstrated that combination oral 

contraceptives and the addition of progestins 

to postmenopausal estrogen replacement 

therapy reduce risk, and this approach could 

be exploited to further reduce mortality 

of type I estrogen-dependent cancers. 

Further improvements in early detection, 

particularly for type II cancers, could be 

facilitated by the ease of access to the 

endometrial cavity if early markers of 

malignant transformation were identified. 

CERVICAL CANCER 

Cervical cancer previously was one of the 

leading causes of cancer deaths in women in 

the United States, and this remains the case 

in most nonindustrialized countries. The 

peak incidence of cervical cancer occurs at 

about 40 years, and women who die of this 

disease often leave behind dependent 

children. Sexually transmitted high-risk 

strains of human papillomavirus (HPV) 

have been shown to represent the etiologic 

agents that are mainly responsible for the 

development of these cancers; however, 

other cofactors, such as smoking and 

immune function, also have been identified. 

In industrialized nations, Pap smear screening 

has dramatically reduced cervical cancer 

mortality. The ease of accessibility of the 

cervix and the ability to diagnose and ablate 

preinvasive lesions have been critical factors 

in the success of cervical cancer screening. 

Most of the residual burden of cervical cancer 

mortality in the United States is attributable to 

women who are not screened, but in some 

cases conventional Pap smears fail to detect 

disease at a preinvasive or early invasive 

stage. A number of new approaches are 

emerging that could further decrease cervical 

cancer deaths, including HPV testing, thinlayer Pap smear cytology, new cervical 

imaging methods, chemopreventive agents, 

and vaccines. A major challenge will be to 

determine the most effective means of 

employing these new approaches to reach the 

goal of eradicating cervical cancer. These 

methods could also be used to address more 

economically the management of women with 

low-grade cervical intraepithelial neoplasia 

(CIN) and atypical squamous cells of 

undetermined significance (ASCUS). 

RESEARCH PRIORITIES 

Priority 1: Define populations at high risk for 

all gynecologic cancers in which screening 

and prevention can be focused. 

Rationale 

Development of the most effective screening, 

early detection, and prevention strategies for 

all gynecologic cancers would be facilitated 

by an improved ability to define subsets of 

women who are at increased risk. This is 

particularly germane to ovarian and endometrial cancers, which have a relatively low 

incidence and are responsible for only a small 

fraction of all cancer deaths. Screening for 

and prevention of these cancers would be 

most cost-effective if these strategies could be 

directed toward populations at increased risk. 

Some of the epidemiologic risk factors (e.g., 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 83 
reproductive events, estrogen exposure) and 

genetic risk factors (e.g., BRCA1/2, DNA 

repair genes) for these cancers have been 

identified, but more work is needed to 

extend this knowledge to the point where we 

can identify workable high-risk populations 

in which to target screening and prevention. 

Areas of investigation that have the potential 

to augment our knowledge in this area 

include the role of common genetic polymorphisms and factors that modify genetic 

susceptibility. Although highly effective 

screening methods exist for cervical cancer, 

new technologies abound and a major issue 

now is how to best focus these in the most 

cost-effective manner. One possibility is to 

stratify women into different screening 

and/or prevention algorithms on the basis 

of their risk of cervical cancer. A better 

understanding of the genetic factors (e.g., 

polymorphisms) and environmental 

exposures (HPV, smoking) that are involved 

in the development of cervical cancer is 

needed to achieve this goal. 

Priority 2: Identify molecular pathways 

and/or surrogate endpoints that can be 

targeted in developing and implementing 

screening and prevention strategies for all 

gynecologic tumor types. 

Rationale 

Understanding the molecular etiologies 

and pathways involved in gynecologic 

carcinogenesis can provide a rational basis 

for directing screening and prevention 

strategies and resources. Although cytologic 

and viral biomarkers exist for cervical 

cancer risk, more specific molecular markers 

of disease progression are vitally needed to 

refine the large population of women with 

mild dysplasia or HPV infection and to 

focus interventions. Similarly, histologic 

precursors for type I endometrial cancer 

have been identified; however, the rising 

death rate, racial disparities, and risks 

associated with current endometrial cancer 

screening modalities drive the need to identify 

biomarkers for endometrial carcinogenesis. 

Furthermore, endometrial cancer provides a 

model system with which to study the 

molecular pathogenesis of estrogenresponsive tumors. There is an urgent need 

for an effective screening test that can identify 

stage I ovarian cancer. The lack of specific 

symptoms and late stage at diagnosis of 

ovarian cancer have hampered our 

understanding of the precursors of this 

disease. High-throughput and other new 

technologies are poised to help identify a 

panel of biomarkers for the detection of 

ovarian cancer. Further research into the 

functional role of these molecules may allow 

them to serve as surrogate endpoint biomarkers of ovarian cancer progression or as 

targets for preventive strategies. These 

surrogate endpoint biomarkers will be vital to 

the analysis of prevention trials, such as those 

based on epidemiologic observations of 

ovarian cancer risks and risk reduction 

strategies. The striking protection against 

ovarian cancer that appears to be provided by 

oral contraceptives and pregnancy suggests 

that prevention may be a feasible approach to 

decreasing mortality, but the lack of surrogate 

endpoints and well-validated animal models 

represent significant obstacles to their 

evaluation. 

Priority 3: Identify the most effective and 

economical means of eradicating the residual 

burden of cervical cancer deaths. 

Rationale 

Conventional Pap smear screening has been 

widely adopted in the United States and 

other industrialized countries, and this has 

translated into a striking decline in cervical 

cancer mortality. A number of new 

approaches are emerging that could further 

decrease cervical cancer deaths, including 

HPV testing, thin-layer Pap smear cytology, 

new cervical imaging methods, chemopreventive agents, and vaccines. We may be 

84 Report of the Gynecologic Cancers Progress Review Group 
about to witness a major paradigm shift in 

which some or all of these approaches are 

incorporated into the prevention, detection, 

and management of preinvasive cervical 

disease. Perhaps the most significant 

challenge in the next decade will be to 

determine the most effective and economical 

means of employing these new approaches 

to reach the goal of eradicating cervical 

cancer deaths in the United States. It is 

conceivable that the optimal approach may 

vary between rural and urban environments 

or between various racial and ethnic groups. 

Hopefully, lessons learned in the United 

States will be useful in addressing the 

enormous worldwide burden of cervical 

cancer. 

BARRIERS 

Difficulties in achieving the goals outlined 

here include the following: 

• The current composition of many 

National Institutes of Health (NIH) study 

sections does not provide the expertise 

needed to knowledgeably evaluate 

proposals on screening and prevention. 

• There is a need for increased funding 

and dedicated funds for screening and 

prevention studies. 

• Primary care physicians and health 

maintenance organization leaders need 

to be better educated about current 

screening and prevention guidelines and 

ongoing research needs. Because most 

early cancers are diagnosed by primary 

practitioners in the community, as 

opposed to in academic medical centers, 

targeting these caregivers may allow 

increased access to early cancers. 

RESOURCES 

Existing funding mechanisms and study 

resources could be better harnessed to focus 

efforts on the screening and prevention of 

gynecologic cancers: 

• Specialized Program of Research 

Excellence (SPORE) grants (in ovarian 

and gynecologic cancers) and the Early 

Detection Research Network could 

intensify their efforts on all gynecologic 

cancers. 

• The Prostate, Lung, Colorectal, and 

Ovarian Cancer (PLCO) Screening Trial, 

the Women’s Health Initiative, and the 

Nurses’ Health Study represent large 

ongoing studies that already have large 

serum banks that may be useful for testing 

and validating new biomarkers. Improving access to these valuable resources is 

important to advancing the field. 

• The Gynecologic Oncology Group may be 

able to provide access to patients to help 

validate new markers if funding to collect 

these specimens are made available. 

• Career development awards or other 

funding mechanisms are required to 

attract young investigators into the field. 

To retain these investigators in the 

screening and prevention fields will 

require additional and dedicated 

funding for studies that address these 

issues. 

• The field would also be enhanced by 

improved mechanisms to encourage 

collaborations with physical scientists, 

including engineers, chemists, and 

physicists, who can bring a different skill 

set and knowledge base to this area. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 85 
• Quality tissues (enhanced with earlystage tumor tissues), serum banks (with 

serial samples in both diseased and 

nondiseased individuals), and linked 

epidemiologic and clinical data are 

much-needed resources. Increased 

funding to encourage quality banking of 

these samples is critical. Likewise, 

for the development of chemoprevention 

strategies. 

• Patient advocates are passionate about 

the importance of early detection and 

prevention. Their energies and voices 

are important resources to increasing 

funding and awareness for these studies. 

86 Report of the Gynecologic Cancers Progress Review Group 
Treatment, Clinical Trials, Gene Therapy, Staging, and Surgery 

Co-Chairs: Richard Barakat, Loretta Itri, and James Tate Thigpen 

Participants: 

Ronald Alvarez Larry Copeland Cornelia Trimble 

Mark Brady Ralph S. Freedman Judith Wolf 

Richard Buller Deborah Jaffe 

Robin Chin Carolyn Muller 

BACKGROUND: STATE 

OF THE SCIENCE 

Large clinical trials have established the 

current standard of care for the three most 

common gynecologic cancers: epithelial 

carcinoma of the ovary, carcinoma of the 

cervix, and endometrial carcinoma. From 

1976 through 2000, a series of large staging 

studies and large phase III trials of the 

Gynecologic Oncology Group have defined 

patient populations for study and have 

demonstrated incremental improvements in 

the management of these cancers. The large 

staging studies represented concerted efforts 

to systematically assess the surgicalpathological staging of patients with 

carcinomas of the ovary, cervix, and 

endometrium. Data obtained from uniform 

surgical assessments and carefully reviewed 

pathologic analysis formed the basis for 

categorization of patients into groups of 

similar prognoses that were amenable to 

similar therapies. Phase III trials in each of 

these groups then identified optimal 

therapeutic approaches for each group. 

In ovarian carcinoma, phase III trials have 

focused on three major groups of patients: 

those with bulky, advanced disease; those 

with minimal residual, advanced disease; 

and those with high-risk, limited disease. In 

bulky, advanced disease, trials have shown 

that the addition of first the platinum 

compounds and then the taxanes to frontline therapy resulted in successive 30 percent 

reductions in mortality. After further 

refinement of the regimen of choice with 

additional phase III trials, the current standard 

of care is a combination of paclitaxel plus 

carboplatin given every 3 weeks for 6 cycles. 

In minimal residual, advanced disease, the 

same regimen is considered the current 

standard of care after appropriate assessment 

of options such as intraperitoneal therapy. In 

patients with high-risk, limited disease, phase 

III trials have finally established the value of 

platinum-based adjuvant chemotherapy. 

In carcinoma of the cervix, four distinct 

groups of patients have been identified: those 

with early disease (preinvasive and early 

invasive disease; stages 0 and IA); those with 

lower-volume stage IB disease; those with 

stage IB bulky through stage IVA disease; 

and those with stage IVB and recurrent 

disease. Relatively few trials of early 

invasive disease have been pursued because 

of the high cure rates that have been achieved 

with surgical resection. Radical hysterectomy 

remains the standard of care in patients with 

stage IB disease amenable to surgical 

resection, although ongoing trials are 

evaluating neoadjuvant chemotherapy. 

Significant improvement in survival has 

resulted from at least five major phase III 

trials of the use of concurrent chemoradiation 

in stages IB–IVA disease. Although trials 

continue to assess systemic approaches for 

patients with stage IVB or recurrent disease, 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 87 
progress in this group has been slow because 

of prior radiation in most of these patients. 

In endometrial carcinoma, surgical staging 

studies identified four distinct groups of 

patients for trials: those with low-risk stage 

IA disease; those with intermediate-risk 

stage IB–II disease; those with high-risk 

stage III–IVA disease; and those with stage 

IVB or recurrent disease. Major phase III 

trials have established a standard of care that 

dictates surgery alone for the low-risk 

patient population, surgery followed by 

pelvic irradiation for the intermediate-risk 

group, and systemic therapy for those with 

stage IVB or recurrent disease. Studies 

continue in the high-risk group with no 

consensus at present. 

In each of these areas, clear progress has 

been made over the last 25 years. The basis 

for this progress has been knowledge about 

the appropriate populations for study within 

each tumor type. The large surgicalpathological staging studies thus have 

provided invaluable guidance over that 25-

year period of clinical investigation. 

In the last decade, however, information 

about the biology of these cancers has 

virtually exploded. It is no longer 

reasonable to base potential therapeutic 

investigation solely on surgical-pathologic 

staging that fails to take into account the 

impact of biologic information on the 

selection of study populations. Two 

potential solutions present themselves. 

Biologic markers can be incorporated into 

the staging system on the basis of collected 

information from a number of small 

trials, but such information suffers from 

inconsistent collection of crucial information 

about the biology of the lesions under study. 

The second solution offers a much better 

alternative. Large staging studies evaluating 

not only the anatomic extent of disease but 

also the biologic characteristics that have 

been identified as potential prognostic 

markers should provide valuable information 

collected in a consistent fashion in a uniformly assessed group of patients. Such 

information will allow for the development of 

a “molecular staging” system that will allow 

better definition of patient populations for 

targeted, biologically based therapy. With 

biologic information integrated appropriately 

into the definition of patient populations, the 

development of appropriate treatment trials 

should follow in a logical fashion. 

In the interim, while such staging studies are 

evolving new molecular staging systems, 

priorities for clinical trials that will further 

improve current therapy should be addressed. 

The following recommendations are divided 

into primary recommendations, which have 

broad implications for the field of gynecologic cancer, and secondary recommendations, which focus on specific tumor types 

and important current clinical questions. 

RESEARCH PRIORITIES 

PRIMARY RECOMMENDATIONS 

Priority 1: Perform large staging trials in 

each of the three major gynecologic cancers 

for the purposes of evaluating current 

molecular markers as integral features of 

staging (“molecular staging”) and of storing 

specimens for evaluation of future molecular 

markers. 

Rationale 

The accurate definition of patient populations 

for specific interventions is critical to the 

proper use of biologically targeted therapy, 

which is likely to be the mainstay of future 

treatment approaches. Current anatomic 

staging systems do not define patient 

populations in a way that is consistent with 

the application of targeted therapies. 

Refinement and revision of current staging 

systems to take into account molecular 

markers is crucial and will require new, large 

88 Report of the Gynecologic Cancers Progress Review Group 
staging studies to collect specimens from 

patients with clinical outcome information 

so that proper clinical correlation can be 

done. The information from these trials will 

form the basis for molecular staging and 

appropriate design of trials to evaluate 

biologically targeted interventions. 

Barriers 

Availability of a tissue bank capable of 

storage and quality assessment of specimens 

for adequacy for studies of DNA, RNA, 

protein, and microenvironment 

Resources 

• Funding for patient accrual and tissue 

acquisition 

• Funding for laboratory studies of 

appropriate biologic markers 

• Funding for tissue bank 

• Biologic knowledge to identify 

appropriate biologic markers to study 

Priority 2: Develop, through appropriate 

randomized trials, imaging techniques 

that can replace more invasive staging 

techniques and provide precise staging 

information. 

Rationale 

Accurate staging is crucial to the proper 

evaluation of patients to be entered into 

clinical trials. The process currently 

requires invasive approaches to the 

assessment of the extent of disease. 

Replacement of invasive procedures with 

accurate imaging techniques can 

substantially reduce patient morbidity and, 

in some instances, mortality. A further 

advantage of staging that does not require 

major invasive procedures is an increase in 

accrual to clinical trials. Many patients are 

currently lost because they are referred to the 

investigative center only after surgery that is 

inadequate for staging purposes. It is much 

easier ethically to recommend imaging studies 

to establish stage than to advocate additional 

surgery solely for staging purposes. 

Barriers 

• Equipment 

• Knowledge of appropriate target 

molecules 

Resources 

• Access to surgically staged patients 

• Equipment and personnel to perform 

required imaging 

Priority 3: The National Cancer Institute 

(NCI) should provide to Cancer Cooperative 

Group chairs discretionary funds to permit 

funding of tissue acquisition and translational 

research studies as an integral part of multiinstitutional clinical trials. 

Rationale 

The true test of a translational research idea is 

a phase III trial. The only setting in which 

this can be done expeditiously and on a 

sufficiently large scale to allow the detection 

of reasonable differences is in a multiinstitutional trial. The translational research 

must proceed concurrently with the clinical 

aspects of the trial; hence, appropriate funding 

must be available on a timely basis. The 

current NCI grant mechanism leads to delays 

and often loss of the translational endpoint. A 

discretionary fund appropriately administered 

by the Cooperative Group chair (a process 

that could easily be reviewed by the NCI) is 

the only way to ensure that the translational 

study will proceed. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 89 
Barriers 

Willingness of NCI to assign adequate funds 

Resources 

• Appropriate merit review process within 

each cooperative group 

• Necessary discretionary funds 

SECONDARY RECOMMENDATIONS 

These recommendations include more 

specific suggestions about studies of each 

tumor type and about the method of funding clinical investigations on a multiinstitutional level. Each recommendation, 

other than the funding recommendation, 

represents a special opportunity within a 

specific tumor type and pertains only to the 

indicated tumor type. 

Ovarian Carcinoma 

Recommendation 1: In advanced disease, 

treatment trials should focus on two areas 

of potential improvement in outcome: 

development of better primary therapy and 

identification of effective consolidation 

strategies. Although primary therapy has 

improved with the addition of, first, the 

platinum compounds and, then, the taxanes, 

expected pathologically complete response 

rates are only 50 percent in minimal residual 

disease and 25 percent in bulky disease. 

With the marked increase in new active 

agents, it is reasonable to expect further 

improvement in primary therapy. At the 

same time, because over half of patients who 

achieve a pathologically complete response 

eventually relapse, there is a need for 

effective consolidation strategies. So that 

consolidation trials will not interfere with 

the interpretation of front-line studies, 

patients for consolidation trials should be 

drawn from those who receive front-line 

therapy outside of clinical trials and present 

for further recommendations after achieving a 

clinically complete response. 

Recommendation 2: In limited disease, 

better definition of the high-risk patient 

population represents the most urgent need in 

order to identify those patients most likely to 

benefit from adjuvant therapy. A large study 

of the role of molecular markers in identifying 

such a population is thus a high priority. 

Recommendation 3: The rapid assessment 

of new biologic (non-cytotoxic) agents as 

potential elements in front-line therapy requires the identification of a population of 

patients who are appropriate for phase II 

trials of combinations of these agents with 

platinum-based chemotherapy. Platinumsensitive patients with long treatment-free 

intervals (> 12 months) afford an opportunity 

for such studies. The development of such 

studies within the Cooperative Group context 

should be a priority. 

Cervical Carcinoma 

Recommendation 1: Emphasis in clinical 

research should be placed on further 

enhancement of efforts to prevent cervical 

cancer. These efforts should include studies 

of barriers to screening in underserved 

populations. The rationale for this 

recommendation is simply that this disease is 

potentially completely preventable. 

Recommendation 2: In recognition of the 

fact that some patients will fail to seek 

appropriate screening, trials to build on the 

success of concurrent chemoradiation in 

patients with locally advanced disease should 

be a priority. Reasonable approaches in this 

area include efforts to develop more effective 

chemotherapy regimens to employ with 

radiation, as well as studies of the potential 

role of non-cytotoxic agents in combination 

with chemoradiation. 

90 Report of the Gynecologic Cancers Progress Review Group 
Recommendation 3: Patients at high risk 

for the development of carcinoma of the 

cervix should be the focus for studies of 

vaccines directed against human 

papillomavirus. Carcinoma of the cervix 

represents an ideal tumor for such studies 

because of the availability of target 

molecules to which vaccine can be directed. 

Recommendation 4: Recent retrospective 

data suggest that maintaining an adequate 

hemoglobin level through the combined use 

of transfusion and erythropoietin results in a 

further 25 percent reduction in mortality 

with the use of concurrent chemoradiation. 

Studies should be undertaken to ascertain 

the factors that account for this improvement and to validate these observations in 

prospective randomized trials. 

Endometrial Carcinoma 

Recommendation 1: Studies should focus 

on patients with aggressive forms of 

endometrial carcinoma rather than on those 

with common, low-grade, endometrioid 

endometrial carcinomas. Such aggressive 

lesions include papillary serous carcinomas, 

clear cell carcinomas, and all grade 3 

carcinomas. The rationale for this recommendation is that these lesions account for a 

disproportionately higher number of deaths 

than do the more common lesions. 

Recommendation 2: Current active 

systemic agents include a limited number of 

drugs: the anthracyclines, the platinum 

compounds, paclitaxel, and progestins. The 

development of effective systemic therapy for 

both advanced disease and the aggressive 

forms of limited disease requires more active 

agents; hence, the assessment of new drugs, 

both cytotoxics and non-cytotoxics, is a high 

priority. 

Recommendation 3: Recent retrospective 

data suggest that maintaining an adequate 

hemoglobin level through the combined use 

of transfusion and erythropoietin results in a 

further improvement in outcome with the 

use of both chemotherapy and concurrent 

chemoradiation. Studies to ascertain the 

factors that account for this improvement and 

to validate these observations in prospective 

randomized trials should be undertaken in 

women with endometrial carcinoma as well 

as carcinoma of the cervix. 

CLINICAL TRIALS FUNDING ISSUES 

Recommendation: Accrual to studies is the 

single most important issue in large phase III 

trials. At present, less than 10 percent of 

patients with gynecologic cancers actually 

enter clinical studies. The experience of the 

Gynecologic Oncology Group suggests that 

funding of patient acquisition through a percapita payment rather than a grant mechanism 

results in significant increases in accrual 

through the incentive to offer trials to more 

patients. The NCI should explore a percapita funding mechanism for all Cancer 

Cooperative Group trials as a means to 

increase further accrual to studies. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 91 
Cervical Cancer 

Co-Chairs: Edward Partridge and Jane Weeks 

Participants: 

Barbara Andersen Yi-Shin Kuo Groesbeck Parham

John D. Chapman Robert Lenkinski Mark Schiffman 

Louise Chow Charles Levenback Ellen Sheets 

Peggy A. Crowley-Nowick Douglas R. Lowy Diane Solomon 

Mona Fouad John McPherson Judith Wolf

Diana Patricia Garcia Marc S. Mendonca Aaron Wolfson 

Lester Gorelic Carolyn Muller 

Diana Jeffery Pat Newman 

BACKGROUND 

Despite the dramatic decline in the incidence 

of and mortality from cervical cancer over 

the last 30 to 40 years, the disease remains a 

significant burden, both worldwide and in 

certain U.S. populations. We lack a full 

understanding of the molecular biology of 

human papillomavirus (HPV) and of the 

role of local and systemic immune responses 

in controlling the development of truly 

preneoplastic lesions. This has led to 

significant over-evaluation and overtreatment of women who probably have a 

reversible infectious process rather than an 

irreversible preneoplastic condition. It is 

thus essential to improve our understanding 

of the process of carcinogenesis. This 

knowledge will lead to more selective 

therapy and the development of preventive 

vaccines. 

HPV testing has demonstrated excellent 

sensitivity for detecting cervical intraepithelial neoplasia (CIN) II and III 

lesions. Its role in cost-effective screening 

and evaluation of women must continue to 

be examined in the United States and 

worldwide. 

The marked differences in the incidence and 

outcome of cervical cancer are attributable to 

multiple factors, including race, ethnicity, 

income, age, and education. These disparities 

must be fully and completely studied (within 

the context of biologic, sociocultural, health 

systems, and health provider factors) in order 

to design the interventions necessary to 

eliminate the gaps. 

Significant advances have recently been made 

in the treatment of locally advanced cervical 

cancer with the addition of chemotherapeutic 

agents and radiosensitizers. A full understanding of the radiobiology and molecular 

events that have led to this improvement 

could further advance our knowledge and the 

potential to cure more advanced disease. 

Although the dramatic reduction in incidence 

and mortality for cervical cancer is a true 

success story, the viral etiology of this 

disease, the accessibility of the organ for 

study, the rapid development of molecular 

biology, and the recognition that more must 

be done to screen certain populations present 

a tremendous opportunity to eliminate this 

disease in the United States and perhaps 

worldwide. 

92 Report of the Gynecologic Cancers Progress Review Group 
RESEARCH PRIORITIES 

Priority 1: Conduct population-based 

studies of quality of care and short- and 

long-term outcomes, with a special 

emphasis on health disparities. 

Rationale 

Little is known about quality of care and 

outcomes in women with gynecologic 

cancers. Seventeen percent of all cancer 

survivors have had a gynecologic cancer, 

but only 3 percent of cancer survivorship 

research grants focus on gynecologic 

cancers. The majority of women with a 

gynecologic cancer receive their care not 

from gynecologic oncologists, but from 

general gynecologists or general surgeons. 

Therefore, studies of quality and outcomes 

of gynecologic cancer care would provide a 

particularly informative setting in which to 

study the relationships between specialist 

versus generalist care and between volumes 

and outcomes. 

We propose large observational cohort 

studies of newly and previously diagnosed 

gynecologic cancer patients. These studies 

would investigate the impact of targeted 

interventions on patient-centered outcomes, 

the dissemination of state-of-the-science 

therapies into practice, the influence of 

modifiable risk factors, and disparities in the 

delivery of high-quality cancer care. We 

recommend that these studies be conducted 

through the newly created Cancer Care 

Outcomes Research and Surveillance 

Consortium (CanCORS) initiative sponsored 

by the National Cancer Institute (NCI), with 

two modifications. First, it is essential that 

these studies look across the disease 

continuum, from diagnosis through 

treatment to survivorship and end-of-life 

care. Second, these studies must include 

sites with sufficient representation of 

disadvantaged populations to be able to 

examine health disparities in treatment and 

outcomes. 

Priority 2: Conduct research on tumor 

biology and genetic/molecular imaging. 

The results of this research could be used to: 

• Predict and assess treatment response 

• Customize therapy 

Rationale 

The critically important task of accurately 

staging cervical cancer currently requires 

invasive approaches. Noninvasive, 

biologically based strategies have the 

potential to spare patients the morbidity and, 

in some instances, mortality associated with 

current staging strategies. Furthermore, 

optimal treatment for cervical cancer would 

be individualized based on patient- and 

tumor-specific characteristics identified at the 

time of diagnosis. Finally, the ability to detect 

changes in tumor biology that occur during 

treatment would allow a dynamic, 

individualized approach to treatment with 

radiation therapy. 

Priority 3: Characterize the molecular 

features of gynecologic cancers and identify 

the molecular pathways and surrogate 

biomarkers involved in gynecologic cancers, 

including those relevant to HPV and its role 

in cervical carcinogenesis. 

Rationale 

Understanding the molecular etiologies 

and pathways involved in gynecologic 

carcinogenesis can provide a rational basis 

for directing screening and prevention 

strategies and resources. Although cytologic 

and viral biomarkers exist for cervical cancer, 

more specific molecular markers of progression are needed to refine the large 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 93 
population of women with mild dysplasia 

or HPV infection and to focus interventions. 

High-throughput and other technologies can 

help identify a panel of biomarkers for 

cancer detection, progression, and response 

to therapy. Such surrogate endpoint 

biomarkers will be vital to the analysis of 

prevention trials such as those based on 

observation of risks and risk-reduction 

strategies. 

Priority 4: Develop vaccines for both 

prevention and treatment of cervical cancer. 

Such vaccines will require: 

• Research to better understand the 

immune microenvironment in the genital 

tract 

• Clinical translation of immune-based 

therapies 

• Targeting of specific tumor antigens 

Rationale 

Vaccine development is underway in 

cervical cancer, but a thorough understanding of immunity as it relates to 

cervical carcinogenesis is necessary. The 

understanding of the role of endogenous 

factors (such as hormones) and exogenous 

factors (such as other pathogens and 

smoking) on immunity is also needed. It 

will be important to examine both systemic 

immunity and immune responses at the 

mucosal surface or the site of neoplasia. 

Vaccine research should include the 

development of laboratory and biologic 

correlates for vaccine response; a 

differentiation of immune response to a 

virally infected cell and a cancer cell; 

differences between HPV-specific 

immunity and cervical-cancer–specific 

immunity; and immunologic profiling 

at cellular and molecular levels to 

discern which women develop chronic HPV 

infection. Finally, research should determine whether HPV is a sufficient target or 

whether other tumor antigens are involved in 

malignant transformation. 

Priority 5: Develop and test screening and 

prevention strategies for use in high-risk 

populations. 

Rationale 

Although highly effective screening methods 

already exist for cervical cancer, the abundance of new technologies raises the major 

issue of how to focus these emerging methods 

in the most cost-effective manner. Development of more effective screening tests, as well 

as early detection and prevention strategies, 

would be facilitated by an improved ability to 

define subsets of high-risk women. We need a 

better understanding of the genetic factors and 

environmental exposures (e.g., HPV and 

smoking) that are involved in the 

development of cancer. 

Priority 6: Assess health disparities in 

cervical cancer incidence and outcomes. 

Research should include database studies, 

population-based cohort studies, and indepth qualitative studies, including patient 

and provider interviews. Such research 

would determine the relative contributions 

of risk factors, screening, treatment, and 

survivorship. 

Rationale 

Several institutions, including NCI, the 

American Cancer Society, and the Centers 

for Disease Control and Prevention have 

placed a major emphasis on eliminating the 

marked disparities in the incidence and 

outcome of cervical cancer over the next 

10–15 years. To accomplish this, we must 

understand the influence of factors underlying these disparities. 

94 Report of the Gynecologic Cancers Progress Review Group 
Priority 7: Conduct intervention research to 

decrease sexual dysfunction and to improve 

fertility outcomes. 

Rationale 

Longitudinal research has documented that 

as many as 50 percent of patients with 

gynecologic cancer experience significant 

sexual dysfunction after diagnosis and 

treatment. Difficulties arise during the 

immediate post-treatment period and, if left 

untreated, these problems do not resolve and 

may worsen over time. When sexual 

difficulties are studied in the context of 

other life areas (e.g., mood, social 

adjustment, employment), they remain an 

“island” of disruption in an otherwise 

generally positive survivorship environment. 

With a substantial research base of 

descriptive efforts on such outcomes, it is 

now appropriate to begin intervention 

studies to prevent or ameliorate these 

difficulties. Of additional concern for many 

young cancer patients are issues surrounding 

fertility after treatment; this area should also 

be explored through intervention research. 

Priority 8: Understand the mechanisms of 

effective combination therapies. 

Combining chemotherapy and radiation 

therapy has recently been shown to improve 

outcomes in patients with advanced cervical 

cancer. To capitalize on this progress, we 

must better understand the mechanisms 

behind the effectiveness of this therapy 

combination, as well as others. To that end, 

future research should: 

• Select the optimal techniques for 

quantifying the biology and genetics of 

cervical cancer radioresistance and 

modify individualized treatments to 

target their dominant mechanisms 

• Evaluate new approaches to the use of 

radiation therapy in non-conventional 

ways 

• Investigate additional ways to combine 

therapies to optimize outcomes 

• Identify tumor characteristics that 

correlate with which tumors are most 

amenable to specific combinations of 

therapies 

Rationale 

This research could lead to individualized 

therapy when appropriate, based on patientand tumor-specific characteristics. 

BARRIERS 

The following key areas were identified as 

barriers or challenges to achieving the 

priorities: 

• Funding principles that discourage 

collaboration 

• Inconsistent and restrictive policies 

concerning informed consent 

• Professional and public ignorance 

regarding cancer genetics research, 

epidemiologic studies, and clinical trials 

• Economic disincentives 

• Unfunded mandates to collect specimens 

• Availability and access to high-quality 

tissue specimens 

• Incomplete and inconsistent phenotypic 

data associated with specimens 

• Small study populations and geographic 

variability in cancer incidence requiring 

national collaborations 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 95 
• Geographic inconsistencies in the 

quality of tumor registry data 

RESOURCES 

The following resources are needed 

to advance cervical cancer priorities: 

• Validated preclinical models (in vitro 

and in vivo) 

• Biological specimen repositories 

for the collection, storage, and 

distribution of well-characterized 

clinical samples 

• Cross-disciplinary training and support for 

individuals with commitment to research 

in gynecologic cancers 

96 Report of the Gynecologic Cancers Progress Review Group 
Endometrial Cancer 

Co-Chairs: Michael A. Friedman and Karl Podratz 

Participants: 

Ruedi Aebersold Lora Hedrick Ellenson Kevin G. Osteen 

Carolyn M. Ballard Holly Gallion Martha C. Romans 

Richard Barakat Paul Goodfellow Susan L. Scherr 

William T. Beck Hedvig Hricak Branimir I. Sikic 

Michael J. Birrer Kimberly Leslie James Tate Thigpen 

Jeff Boyd Franco Muggia John Wiktorowicz 

Robin Chin David Mutch 

Terri Cornelison Peggy Olive 

BACKGROUND AND STATE 

OF THE SCIENCE 

The American Cancer Society estimates that 

approximately 38,000 new cases and 6,600 

deaths will accrue from endometrial cancer 

during calendar year 2001. The link between 

estrogen-induced proliferation and 

progesterone-induced differentiation is well 

established in normal endometrium. 

Whereas hormonal regulation is initiated via 

receptor assembly, ligand binding, and 

interactions with coregulators and the 

transcriptional machinery, the functional 

identifiable hormone response incorporates 

complex interactions with a multiplicity of 

growth factors that reside in both the 

epithelium and the stroma. 

Our understanding of the etiologic processes 

that predispose to malignant transformation 

in the endometrium is very limited. 

Although the majority of endometrial 

cancers are hormone dependent, the normal 

control mechanisms are nonetheless lost, 

allowing uncontrolled growth, invasion, and 

metastasis. Evidence from breast carcinoma 

suggests that alterations in hormone receptors and changes in the hormonal milieu 

in the microenvironment result in the activation of various growth factor pathways. 

In contrast, hormone-independent tumors 

constitutively appear to activate growth factor 

pathways. These tumors account for a 

minority of the endometrial cancers but 

constitute a more aggressive histologic 

subtype and a decrease response to treatment. 

Our knowledge of the molecular biology in 

this subset, particularly the understanding of 

the “cross-talk” among hormones, specific 

growth factors, hormone and/or growth factor 

receptors, and other modulations, is very 

limited. Furthermore, these molecular 

processes are influenced by interactions 

within both the epithelium and the stroma. 

The expansion of knowledge and an 

understanding of how to manipulate the 

molecular indices of endometrial cancer will 

be facilitated by directed resources 

investigating alterations in oncogene/tumor 

suppressor gene regulation, hormone 

receptors, growth factors, growth factor 

receptors, and other modulators of 

transformation, invasion, and metastasis. At 

present, the investigative community is 

hampered by limited tissue availability with 

accompanying detailed epidemiologic and 

clinical data. Furthermore, animal models 

with validated genetic, histopathologic, and 

behavioral features resembling human 

endometrial carcinoma are not available. 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 97 
Prevention, early detection, and treatment of 

endometrial cancer will be predicated on our 

understanding of the molecular signatures of 

the various histologic subtypes. The process 

of securing this critical fund of molecular 

information will necessitate the design and 

maturation of clinical trials with priorities 

that include clinical staging, long-term 

follow-up, and meticulous collection and 

storage of tissue specimens and the analysis 

and correlation of molecular indices with 

clinicopathologic parameters. These efforts 

will likewise facilitate further clinically 

relevant diagnostic and therapeutic 

approaches. 

RESEARCH PRIORITIES 

Priority 1: Establish a specimen bank as an 

enduring national resource. 

• To provide an efficient, orderly 

framework to evaluate the biologic and 

clinical features of endometrial cancer 

representing large numbers of clearly 

evaluated subjects 

• To foster evaluation of new tests and 

techniques for tissue acquisition and 

storage that allow for more precise tests 

on smaller amounts of tissue (e.g., 

immortalized RNA banks for gene 

expression studies to address limited 

RNA in samples) 

• To identify prognostic and predictive 

markers for treatment efficacy (CT, RT, 

surgery, biologic therapy) and toxicity, 

using populations of patients consistently evaluated, treated, and followed 

• To compare normal endometrium, 

endometriosis, and endometrioid and 

other histologic types of malignancies 

• To access other relevant specimens (e.g., 

blood, serum, lymphocytes) 

• To link to endogenous and exogenous 

risk factors (e.g., reproductive history, 

smoking, and hormone use) 

Currently no such comprehensive resource 

exists. Specific issues for a specimen bank 

include the following: 

• The provision of a long-term, comprehensive national repository will be 

expensive and must be properly funded. 

• Currently there are numerous 

disincentives to specimen collection— 

surgeons, pathologists, and the like must 

be engaged. 

• Far more patient/subject specimens would 

be needed to provide appropriate statistical power and robustness. 

• Legal/ethical concerns for subject 

protection, institution/individual 

indemnification, and commercial rights 

may require legislation or executive 

clarification. 

• There needs to be a “societal will” to 

make this bank a success—patient 

advocates, learned societies, and care 

providers (and their associations) must be 

committed to its success. 

• Correlative clinical data as to staging, 

therapy, and outcomes must be of high 

quality (accuracy). In addition, follow-up 

specimens should be captured where 

feasible. 

• Normal specimens that are appropriately 

matched (epidemiologic) would be highly 

valuable. 

• Provision of specimens should be made 

for fair, equitable distribution of 

specimens to interested investigators 

based on objective criteria. 

98 Report of the Gynecologic Cancers Progress Review Group 
• New assays, hypotheses, and techniques 

to be tested would likewise be evaluated 

and prioritized in a fair, transparent way. 

• Comprehensive information management would be needed to allow for 

powerful correlations, comparisons, and 

analyses. 

Priority 2: Define endometrial tumor 

biology with special attention to unique 

opportunities and features. 

• Understand steroid hormone receptor 

expression, assembly, degradation, and 

modulation in normal and malignant 

states. Understand interactions between 

steroid and polypeptide hormones, 

growth factors, and various receptors 

(cross-talk). 

• Understand epithelial-stromal 

interactions for tumor growth and 

invasion (including aromatases, 

dehydrogenases, sulfatases, growth 

factors). 

• Take advantage of the knowledge of 

cycling endometrium and characterize 

blood vessel biology for normal and 

tumor vessels. There are clinically 

exploitable interventions and specific 

molecular probes with which to evaluate 

VEGF, PDGF, FGF, integrin, and MMPI 

mechanisms. 

• Characterize the immunologic 

microenvironment for endometrial 

cancer and endometriosis. 

Priority 3: Develop relevant, validated 

animal models for endometrial cancer, as 

none currently exist. 

• Study genetic, physiologic, and 

environmental pathways, correlating 

histopathology, biologic behavior, and 

molecular features. 

• Study steroid hormone receptors, other 

growth factor receptors, genetic features, 

stromal-epithelial interactions, and 

angiogenic and metastasis mechanisms 

that provide insight into human disease. 

• Provide correlates and leads for imaging 

research efforts. 

Priority 4: Develop imaging methods that 

provide more sensitive, dynamic, and 

functional information in both animal models 

and among women patients. 

• Define the molecular signatures of 

endometrial cancer cells (such as hormone 

receptor, growth factor receptor, or p53 

imaging). 

• Define the physiologic characteristics of 

tumors (e.g., angiogenesis, apoptosis, 

hypoxia, pharmacodynamics of therapy). 

• Identify surrogate markers for: 

—Proof of target studies (e.g., tyrosine 

kinase phosphorylation) 

—Proof of principle (e.g., change in 

angiogenesis) 

—Proof of efficacy (e.g., tumor 

shrinkage) 

• Evaluate all modalities, including: 

—Radiotracers 

—Scintigraphy/SPECT/PET 

—Magnetic resonance imaging and 

magnetic resonance spectroscopy 

—Optical (bioluminescence, optical 

coherence tomography, spectroscopy, 

confocal microscopy) 

—Ultrasound (contrast, microscopy, 

elastography, 3-D) 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 99 
• Conduct intertechnique comparisons, 

standardization, and correlation with 

surgery for the technologies. 

• Implement multidisciplinary collaboration among physicians, biologists, 

chemists, engineers, and biostatisticians 

to provide important insights. 

• Develop techniques for screening 

appropriate populations for early 

diagnosis and prevention studies. 

• Provide accurate, noninvasive staging, 

reevaluation, and response assessment 

information. 

Priority 5: Create a natural history 

database for molecular and clinical 

correlation. 

• Obtain large databases of endometrial 

cancer patients consistently evaluated, 

surgically-pathologically staged, further 

treated as needed, and sufficiently 

followed to provide comprehensive 

disease overview. 

• Utilize a tissue bank (Priority 1) to 

perform molecular biologic 

characterizations so that biologic 

features and clinical outcome can be 

meaningfully related. 

• Correlate, if need be, sensitivity to, 

resistance to, and toxicity of chemotherapy, biologic therapy, and radiation 

therapy. 

Priority 6: Conduct early detection and 

prevention clinical studies. 

• Conduct specific (hypothesis-based) 

prevention studies conducted on 

characterized higher risk populations. 

• Identify molecular pathways/surrogate 

markers that can be targeted for screening and prevention studies. 

• Develop valid surrogate markers of 

clinical outcomes to ease regulatory 

barriers and compress time and investment needed to determine benefit. 

BARRIERS 

The following key areas were identified as 

barriers or challenges to achieve the priorities: 

• Tissue resources: Lack of tissues for use 

in assessing the molecular signatures of 

endometrial cancer. Tissue procurement 

to date has not included normal, 

proliferative, hyperplastic and various 

histologic subtypes of endometrial 

cancers. In addition, the accompanying 

clinical data for correlative studies is not 

readily available. A variety of regulatory 

barriers exist that impede accrual in trials 

securing tissues will need to be addressed. 

• Animal models: Currently no validated 

animal models exist that demonstrate 

genetic, histopathologic and behavioral 

characteristics of the human model. 

• Uniform technology/reagents: There 

exists a lack of readily available reagents 

with sufficient sensitivity and specificity 

with regard to antibodies, imaging probes, 

etc. There exists a need for the development of appropriate surrogates in imaging, 

early detection and other diagnostic and 

treatment areas. 

• Technology/equipment: Currently 

noninvasive staging is limited by the 

sensitivity of imaging reagents and 

equipment. 

• Patient accrual: Clinical trials for early 

detection, prevention and treatment have 

failed to accrue patients with appropriate 

ethnic, economic and geographic 

diversity. Likewise, epidemiologic 

studies involving patients with the highrisk histologic subtypes are not available. 

100 Report of the Gynecologic Cancers Progress Review Group 
RESOURCES 

The following resources were identified in 

order to achieve the priorities: 

• Leverage NIH and other public health 

organizations and initiatives to better 

address endometrial cancer priorities; 

for example: 

— Link to NICHD to co-fund, share 

information, and collaborate on studies 

of normal endometrium, implantation 

(placental) biology, endometriosis, etc. 

— Link to the Office of Women’s 

Health, NIAMS, NHLBI, NIDDK, and 

Indian Health Service to study populations 

of overweight, older women with special 

reference to osteoarthritis, hypertension, 

diabetes, and endometrial cancer 

• Robust commercial interest in diagnostic, 

therapeutic and prevention products and 

techniques of relevance 

• Tissue accessible relatively easily and 

repeatedly; organ extirpation relatively 

frequent, which permits biopsy– 

intervention–resection studies 

• Opportunity to leverage insights from 

breast and prostate cancer biology 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 101 
Ovarian Cancer 

Co-Chairs: David M. Gershenson and Richard J. Zaino 

Participants: 

Ronald Alvarez Judy Garber Sundaram Ramakrishnan 

Robert Bast Barry B. Goldberg Marcus E. Randall 

Deborah Bell Patricia Goldman Neeraja Sathyamoorthy 

Andrew Berchuck Silvia Curtis Hewitt Joellen Schildkraut 

Mark Brady Beth Y. Karlan Mary Jackson Scroggins 

Richard Buller Ann Kolker M. Sharon Stack 

Larry Copeland Robyn Kravit Barbara Vanderhyden 

Mary B. Daly Susan Lowell-Butler Michael Welch 

Mary (Nora) Disis Trish May 

Ralph S. Freedman Samuel Mok 

BACKGROUND: STATE 

OF THE SCIENCE 

Ovarian cancer is the second most common 

gynecologic malignancy, accounting for 

23,400 new cases and 13,900 deaths 

annually. It is the fifth most common cancer 

in women in the United States. Although 

incremental improvement in survival has 

occurred in the past three decades, the 5-

year survival for all stages of the disease is 

only about 40 percent. This low survival rate 

reflects the lack of an effective prevention 

strategy, the failure to detect ovarian cancer 

in early stages, and the inability to cure 

advanced stage disease. Significant 

improvement in survival rates will require 

identification of new strategies for early 

detection and prevention of ovarian cancer. 

Although the etiology of ovarian carcinoma 

is unknown, epidemiological studies have 

demonstrated the protective effects of oral 

contraceptive use and tubal ligation. 

Approximately 10 percent of ovarian 

cancers are hereditary and the remaining 90 

percent are sporadic. 

Lari Wenzel 

Stacey Young-McCaughan 

Ovarian cancer represents a heterogeneous 

group of tumors with varying biologic 

behaviors. Relatively little is known about 

growth signaling pathways, response to 

hormonal influences, mechanisms of 

peritoneal spread, and epithelial-stromal 

interactions in this disease. In contrast to 

carcinomas of the cervix and endometrium, 

no well-defined precursor lesion has been 

identified thus far. Since no effective 

screening method exists, over 70 percent of 

cases are detected after cancer has spread 

beyond the ovary. 

Comprehensive surgical staging has enabled 

us to more precisely define prognosis. 

However, because most women are not 

operated on by gynecologic oncologists, 

incomplete surgical staging remains a major 

problem in the year 2001. 

For stage I low-grade tumors, surgery alone 

provides effective therapy in a majority of 

cases. For all other stages and grades, 

standard treatment consists of primary 

surgery, followed by platinum-based 

chemotherapy. Although metastatic ovarian 

102 Report of the Gynecologic Cancers Progress Review Group 
cancer is moderately sensitive to chemotherapy, there is a high rate of relapse. The 

introduction of taxanes into the therapeutic 

armamentarium has not improved long-term 

survival as much as anticipated. 

Secondary therapy for refractory disease is 

generally ineffective, thus providing an 

important incentive for new drug discovery. 

Since most women with recurrent ovarian 

carcinoma are not cured of their disease, the 

quality as well as duration of survival is a 

critical issue. 

RESEARCH PRIORITIES 

Priority 1: Develop strategies for early 

detection and prevention of ovarian cancer. 

• Define the populations at increased risk, 

due to either hereditary or environmental 

factors, for which screening and 

prevention research should be focused. 

• Develop the most effective screening 

and prevention strategies. 

• Elucidate the genetic influences on 

environmental factors in the 

development of ovarian cancer. 

• Identify the pathways involved in the 

development of both hereditary and 

sporadic cancers. This would include 

characterization of molecular, immunologic, and histologic pathways. Points 

along these pathways might serve as 

surrogate endpoints in future clinical 

studies. 

• Identify biomarkers and develop 

imaging techniques to detect early-stage 

disease. 

Priority 2: Develop high-throughput 

approaches to characterize gene expression 

and function using genomic and proteomic 

technology. 

• Define molecular signatures of ovarian 

carcinoma characterized by histologic 

type and surgical stage. 

• Develop a molecular classification system 

for ovarian cancer. This classification 

system should be independent of cell type 

or histologic grade and be predictive of 

response to therapy and survival. 

• Identify potential molecular targets for 

therapy. 

• Identify markers of sensitivity and 

resistance to therapeutic agents. 

Priority 3: Elucidate mechanisms responsible 

for tumor progression and the regulation of 

metastasis. 

• Understand the interactions of stromal and 

epithelial cells in the normal ovary and in 

the development of ovarian carcinoma. 

• Study the response of both epithelial and 

stromal cells to hormonal stimulation. 

• Elucidate the growth signaling pathways 

responsible for tumor progression and 

metastasis. 

• Determine the role of angiogenesis in 

tumor progression and metastasis. 

• Determine the role of the peritoneal 

microenvironment in modulating the 

immune response at different stages of 

disease. 

• Define the immunogenic proteins in 

ovarian cancer. 

Priority 4: Determine how ovarian cancer 

and its therapy influence quality of life and 

survivorship. 

• Study quality of life in ovarian cancer 

patients, including acute effects of 

Appendix D: Reports of the Gynecologic Cancers PRG Roundtable Breakout Groups 103 
therapy, sexuality, fertility, psychosocial 

health, and late effects of therapy. 

• Study how to provide optimal supportive 

care at the end of life. 

• Study the safety and quality of life 

associated with hormone replacement 

therapy in ovarian cancer survivors. 

• Investigate disparities in access to care, 

quality of care, and outcomes in various 

populations, including underserved 

populations. 

Priority 5: Optimize efficiency of clinical 

trials. 

• Prioritize the study of and ensure access 

to new agents and combination 

strategies. 

• Develop surrogate markers and imaging 

techniques of treatment efficacy. 

• Enhance patient and physician 

participation in clinical trials. 

• Develop pharmacogenomic approaches 

to predict drug response and toxicity. 

BARRIERS 

• Inconsistent and restrictive policies 

concerning informed consent 

• Issues of privacy, confidentiality, access, 

and discrimination for employability and 

insurability 

• Restrictive research regulatory environment for clinical trials and drug 

evaluation 

• Inefficient and lengthy protocol review 

process 

• Professional and public lack of knowledge regarding cancer genetics, epi

demiologic, and clinical trials research 

• Economic disincentives regarding referral 

by community physicians to academic 

medical centers for patient care are 

clinical trials 

• Lack of funding directed toward ovarian 

cancer research 

• Absence of timely funding for translational research linked to clinical trials 

• Limited availability and access to high 

quality tissue specimens 

• Limited access to novel investigational 

agents or combinations of agents 

developed by pharmaceutical firms 

• Inequities in access of underserved 

populations to clinical trials 

RESOURCES 

• High-quality tissue, epidemiologic data, 

follow-up information, early-stage 

samples, and serial samples 

• Generation and validation of models 

• Innovative study design (biostatistical, 

laboratory-based endpoints, epidemiologic, etc.) 

• Career development (outcomes, quality of 

life, clinical trials, laboratory-based) in 

ovarian cancer research 

• Professional and public educational 

programs 

• Centers of excellence in proteomics, 

genomics, and bioinformatics 

• Professional and public education related 

to health disparities 

• Supplemental funding for translational 

research linked to clinical trials 

104 Report of the Gynecologic Cancers Progress Review Group