NATIONAL CANCER INSTITUTE

WOMEN'S HEALTH REPORT
Fiscal Years 1999-2000
March 2001

EXECUTIVE SUMMARY

This report describes many of the activities and accomplishments of the National Cancer Institute's research programs in 1999 and 2000, addressing cancers specific to or primarily affecting women or those cancers with high incidence or mortality among women. Cancers included are breast, cervical, endometrial, ovarian, lung, and colorectal cancers, as well as AIDS-associated malignancies.

Cancer continues to take a devastating toll on American women. By the end of 2001, an estimated 625,000 women will have been diagnosed with cancer, and approximately 267,300 women will have died of the disease. Despite these grim statistics, our Nation is making progress in the fight against cancer. Between 1992 and 1997, our cancer incidence rates dropped significantly, on average nearly 1.3 percent per year with more rapid decreases since 1995. Overall cancer mortality rates for women have been declining since about 1950, however, at the same time, lung cancer mortality has been increasing in women. Breast cancer incidence rates have shown little change in the 1990s, but death rates have declined by about 2 percent per year and have dropped even more since 1995. Of major concern are continued higher incidence and mortality rates among some racial and ethnic groups for some cancers. We have established a number of initiatives, described in the report, which will work to improve understanding of disparities and develop strategies and interventions to overcome them. More people are living with cancer. As of January 1997, there were 8.9 million people, or 3% of the U.S. population, who were cancer survivors. 58% of these were women.

Through its strategic planning process, the NCI has identified many of the questions that need to be answered, areas of research and care that need to be further addressed, and infrastructure that needs to be strengthened in order to advance our knowledge in the study of cancer. In 2000, the NCI formally established an Office of Women's Health. Organizationally located within the Office of Science Planning and Assessment, the Office is responsible for assisting in the planning, evaluation, and coordination of activities related to cancer in women.

The National Cancer Institute (NCI) is committed to continuing efforts to reduce the toll of cancer through scientific discovery and its application to people. The NCI supports and coordinates a comprehensive research program that investigates all aspects of cancer, including biology, risk, prevention, detection and diagnosis, treatment, control, surveillance, and survivorship. In addition to a wide range of research projects directed at cancers that are specific to women, NCI supports a number of broad-based research programs that apply to all types of cancer in both women and men.

Basic research studies exploring the science of how cancer develops form the foundation of cancer research. Through these studies, scientists are identifying, at the molecular and cellular level, the fundamental processes that underlie a cell's transformation from normal to pre-malignant to malignant. The implications of this research are profound; identifying the processes and pathways that lead to cancer provides attractive targets for new prevention, detection, and treatment approaches. In vitro and in vivo models provide valuable tools for studying the development and behavior of cancer. The recently established Mouse Models of Human Cancers Consortium will provide a new interactive research platform to develop and test the validity of preclinical models which will help to elucidate the development and behavior of cancer and to test new approaches to detection, diagnosis, imaging, prevention and treatment.

In order to conduct research which will further our understanding of the processes involved in the development of cancer, critical resources are needed. For example, genetic registries are being developed to provide researchers with valuable resources for conducting important investigations on genetic and environmental susceptibility for cancers and to support investigations in genetic epidemiology, including the identification and characterization of genes and gene-gene and gene-environment interactions important to susceptibility to specific cancers. To identify and evaluate molecular biomarkers and technologies for earlier detection and risk assessment of all major cancers, networks of investigators in the laboratory and clinical sciences, biostatistics, informatics, and public health are already developing new approaches which may result in new, noninvasive screening approaches.

The NCI supports research in areas of cancer prevention, control, and treatment, including studies in nutrition, chemoprevention, biobehavioral influences on disease, cancer screening, pain control, complementary and alternative medicine, cancer survivorship, and understanding health disparities. A number of recently launched initiatives address issues related to ways to improve the quality of cancer care.

NATIONAL CANCER INSTITUTE
Women's Health Report, Fiscal Years 1999-2000
March 2001

INTRODUCTION

This report describes many of the activities and accomplishments of the National Cancer Institute's research programs in Fiscal Years 1999 and 2000, addressing cancers specific to or primarily affecting women, as well as those cancers with high incidence or mortality among women. Cancers included are breast, cervical, endometrial, ovarian, lung, and colorectal cancers, as well as AIDS-associated malignancies.

Cancer continues to take a devastating toll on American women. By the end of 2001, an estimated 625,000 women will have been diagnosed with cancer, and approximately 267,300 women will have died of the disease. Despite these grim statistics, our Nation is making progress in the fight against cancer. Between 1992 and 1997, overall cancer incidence rates in the United States dropped significantly, on average nearly 1.3% per year. Cancer mortality for both men and women declined by 0.6% per year from 1991 to 1995 and fell more rapidly between 1995 and 1997, at a rate of 1.7% per year. Although cancer mortality rates for women have been declining since about 1950, during that time lung cancer mortality rates among women have been increasing. Breast cancer incidence rates showed little change in the 1990s, but death rates have declined by about 2% per year and have dropped even more since 1995.

Statistics also show that more people are living with cancer. As of January 1997, 8.9 million people, or 3% of the U.S. population, were cancer survivors, and 58% of these individuals were women. Of major concern are continued higher incidence and mortality rates among some racial and ethnic groups. A number of factors may contribute to these disparities. To coordinate the efforts of the National Cancer Institute's (NCI's) Health Disparities Plan (http://ospr.nci.nih.gov/healthdisprpt.pdf), in 2000 the Institute established the Center to Reduce Cancer Health Disparities. The NCI has also established a number of initiatives that will work to improve understanding of health disparities and develop strategies and interventions to overcome them.

The NCI is committed to continuing efforts to reduce the toll of cancer through scientific discovery and its application to people. To that end, the Institute supports and coordinates a comprehensive research program that investigates all aspects of cancer, including biology, risk, prevention, treatment, control, surveillance, and survivorship. In 2000, the NCI formally established an Office of Women's Health. Organizationally located within the Office of Science Planning and Assessment, the Office of Women's Health is responsible for assisting in the planning, evaluation, and coordination of activities related to cancer in women.

In addition to a wide range of research projects directed at cancers that are specific to women, the NCI supports a number of broad-based research programs that apply to all types of cancer in both women and men. Through its strategic planning process, the NCI has identified many of the questions that need to be answered, areas of research and care that need to be further addressed, and infrastructure that needs to be strengthened to advance our knowledge in the study of cancer. The Nation's Investment in Cancer Research: A Plan and Budget Proposal for Fiscal Year 2002 (http://plan2002.cancer.gov) includes descriptions of these high-priority areas. The initiatives are not, for the most part, disease specific but address problems and opportunities that are common to all tumors and emphasize the development of technologies and approaches that are applicable to many cancers. As part of the planning process, the NCI convenes Progress Review Groups to assist in setting priorities for organ site-specific research. Since 1998, Progress Review Group reports have been completed in breast, prostate, colorectal, and pancreatic cancers; brain tumors; and lymphoma, leukemia, and myeloma. Reports of these groups are available at http://prg.nci.nih.gov. Progress Review Groups are either in progress or planned for lung, gynecologic, kidney and bladder, skin, stomach and esophageal, and liver and bile duct cancers.

CROSS-CUTTING INITIATIVES

CANCER BIOLOGY AND GENETICS

Basic research studies that explore the science of how cancer develops form the foundation of cancer research. Through these studies, scientists are identifying, at the molecular and cellular levels, the fundamental processes that underlie a cell's transformation from normal to pre-malignant to malignant. The implications of this research are profound: identifying the processes and pathways that lead to cancer provides attractive targets for new approaches to prevention, detection, and treatment.

Cancer researchers are studying key processes such as angiogenesis (the formation of new blood vessels) and the signaling pathways involved in cell division and cell death, all of which are critical to tumor development and growth. In collaboration with the Center for Biologics Evaluation and Research of the Food and Drug Administration (FDA), the Tissue Proteomics Initiative seeks to develop and utilize new technology to analyze proteins and pathways in human tissues from pre-malignant through treatment phases of disease. In vitro and in vivo models provide valuable tools for studying the development and behavior of cancer. The NCI recently established the Mouse Models of Human Cancers Consortium, providing funding to 19 groups of investigators at more than 30 U.S. institutions. The consortium will provide a new interactive research platform on which to develop and test the validity of preclinical models that will help to elucidate the development and behavior of cancer and to test new approaches to detection, diagnosis, imaging, prevention, and treatment.

Studies in cancer genetics are providing unprecedented insight into the development and evolution of cancer and are generating knowledge about the most basic processes involved in the onset of this disease. The NCI has established a number of initiatives to provide infrastructure and stimulate research to define the signatures of cancer cells. These include the Cancer Genome Anatomy Project (CGAP) and its component initiatives. Information generated by CGAP research is available to the scientific community. (More information on CGAP can be found at http://www.ncbi.nlm.nih.gov/ncicgap.) In 1998, the NCI established the Cancer Genetics Network (http://cancercontrol.cancer.gov/CGN), a national network of centers specializing in the study of inherited predisposition to cancer. The Network supports collaborative investigations into the genetic basis of cancer susceptibility, mechanisms to integrate this new knowledge into medical practice, and means of addressing the associated psychosocial, ethical, legal, and public health issues. The Cancer Family Registries for Breast and Colorectal Cancers (http://www-dccps.ims.nci.nih.gov/EGRP/cfr.html) provide resources for investigating genetic and environmental susceptibility for these cancers. The Registries also support investigations in genetic epidemiology, including the identification and characterization of genes and gene-gene and gene-environment interactions that are important to susceptibility to breast, ovarian, and colorectal cancers. To identify and evaluate molecular biomarkers and technologies for earlier detection and risk assessment of all major cancers, the NCI established the Early Detection Research Network (http://edrn.nci.nih.gov). This national network of investigators in the laboratory and clinical sciences, biostatistics, informatics, and public health are already developing new approaches that may result in new, noninvasive screening approaches.

TRENDS IN CANCER

As the U.S. population continues to increase and age, and despite continuing decreases in cancer incidence and mortality, cancer will continue to be an increasing burden on our health care systems for the foreseeable future. Accurate information about the incidence and impact of the disease are critical to decision making in science and public health. Within the NCI, the Surveillance Research Program collects and disseminates information on changing U.S. cancer trends (http://www-seer.ims.nci.nih.gov). In 2000, NCI's surveillance efforts were expanded to cover a broader spectrum of the racial, ethnic, socioeconomic, and cultural diversity of our country. The Surveillance, Epidemiology, and End Results (SEER) program will add four new population-based registries in geographic areas populated by minorities and medically underserved groups to better capture cancer information on these populations. This expansion also includes coverage of states with high cancer mortality and will expand the U.S. population covered from 14 to 24%. The NCI maintains an Atlas of Cancer Mortality in the United States, 1950-94 (http://www.nci.nih.gov/atlas), which was launched in 1999. It is a unique resource showing the geographic patterns of cancer death rates in more than 3,000 counties across the country over more than four decades. Current collaborations among the NCI, the Centers for Disease Control and Prevention (CDC), the American Cancer Society, the North American Association of Central Cancer Registries, and the National Center for Health Statistics will be enhanced to produce data specific to national, state, and regional areas. These initiatives will improve our national cancer surveillance infrastructure and will provide high-quality cancer incidence data to be used in analysis and reporting based on SEER and non-SEER registry systems.

PATIENT-ORIENTED RESEARCH

Clinical Research

The NCI supports a broad program of clinical research to develop new agents and novel approaches for the prevention, early detection, and treatment of cancer. Clinical trials to evaluate improved and novel prevention, detection, and treatment strategies are carried out within a clinical trials infrastructure that includes the NCI Cancer Centers, Cooperative Groups, Specialized Programs of Research Excellence (SPOREs), and the Community Clinical Oncology Program (CCOP) and minority-based CCOPs. The Institute is currently in the process of fundamentally changing the ways that it develops, reviews, conducts, and supports cancer clinical trials. The revitalized system is more flexible and more inclusive, inviting input from basic and clinical researchers, community and research oncologists, patients and families, and all groups with a commitment to improving cancer care. The new system will speed new ideas from the laboratory to the clinic, increase physician and patient participation, and streamline administration and data reporting. The NCI's efforts to build the new clinical trials system fall into five categories: generating new ideas, broadening access for physicians and patients, educating and communicating, streamlining procedures, and automating data systems.

The NCI supports patient-oriented research in cancer prevention, early detection, diagnosis, and treatment, including studies in nutrition, chemoprevention, biobehavioral influences on disease, cancer screening, pain control, complementary and alternative medicine, cancer survivorship, and understanding health disparities. A number of recently launched initiatives address ways to improve the quality of cancer care. These include the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS), launched in 1999; the Breast Cancer and Colorectal Cancer Surveillance Consortiums; SEER; patterns of care studies; and the HMO Cancer Research Network. These and other quality-of-care initiatives are coordinated from the Division of Cancer Control and Population Sciences (http://cancercontrol.cancer.gov).

Cancer Information

The NCI provides information to cancer patients, health and research professionals, and the public in a variety of formats. The most recent, complete, and reliable information to assist cancer patients, their families, and their health care providers in making decisions about cancer prevention, detection, treatment, and follow-up care is available through print publications and audiovisual materials designed for many cultural and literacy levels; from the Cancer Information Service's (CIS's) toll-free number, 800-4-CANCER; and through its Web site resources, including the CancerNet (http://cancernet.nci.nih.gov) and CancerTrials (http://cancertrials.nci.nih.gov) Web sites. Other sites across the Institute provide information about ongoing research programs and activities. The Office of Cancer Survivorship (http://survivorship.cancer.gov) provides information for researchers and survivors, including an overview of current research, funding and training opportunities, and new research directions, as well as a resource list of programs for survivors and links to related articles, data (including cancer prevalence data), and press releases.

In May 2000, the NCI's communications activities were restructured and expanded by the creation of an integrated, technology-based Office of Communications. The new organization will enhance the Institute's capabilities in Web design and evaluation, maximize the use of emerging technologies, optimize the ability to provide information to people with questions about cancer, and increase the NCI's ability to form partnerships with outside organizations. Research programs funded by the NCI's Division of Cancer Control and Population Sciences coordinate and support research in Health Communication and Informatics; and Health Promotion Research. Examples of initiatives in progress or under development include funding for Centers of Excellence in Cancer Communications Research (http://cancercontrol.cancer.gov/communicationcenters), Digital Divide Pilot Projects, and projects focused on maximizing effective communication about cancer through message tailoring, as well as a demonstration project with the Agency for Healthcare Research and Quality to enhance consumers' and patients' use of information about health care quality.

ADDRESSING HEALTH DISPARITIES

The NCI is strongly committed to reducing cancer-related health disparities across the cancer continuum, from prevention to end-of-life care. The Institute supports research to understand the complex causes of disparities in cancer risk, incidence, and mortality, including socioeconomic, cultural, environmental, institutional, behavioral, and biological factors. The NCI also devotes resources to the application of research, education and training programs, and working with underserved communities to translate research evidence into improved health outcomes. As a partner in the national cancer effort, the NCI is also planning new initiatives with other Federal agencies, local governments, and private entities to disseminate effective, evidence-based interventions to reduce cancer-related health disparities and improve the health and well-being of underserved communities. Many of these initiatives are described in the FY2002 Plans and Priorities for Cancer Research (http://plan2002.cancer.gov/infreduce.htm), published in the fall of 2000. The Institute's overall goal is to understand the causes of health disparities in cancer and to develop effective interventions to eliminate these disparities.

As part of the implementation of the Strategic Plan to Reduce Health Disparities (http://ospr.nci.nih.gov/healthdisprpt.pdf), the NCI has created the Center to Reduce Cancer Health Disparities. The Center will provide an organizational locus for the critical tasks needed to translate discovery into delivery. A number of initiatives are either in place or being established. Of high priority is a project focusing on understanding the causes of and developing interventions to address high rates of cervical cancer in rural communities. Expansion of the SEER cancer registry to cover more of the diversity of the United States will provide better information for tracking trends in health disparities. In 2000, the Special Populations Networks for Cancer Awareness Research and Training (http://cancercontrol.cancer.gov/spn) funded 18 grants at 17 institutions to create or implement cancer control, prevention, research, and training programs in minority and underserved communities. The cooperative relationships established by the Networks will be used to foster cancer awareness activities, support minority enrollment in clinical trials, and encourage and promote the development of minority junior biomedical researchers. This initiative, one of the largest of its kind in the Federal Government, is designed to encourage people from the community to work with scientists to find ways of addressing important questions about the burden of cancer in minority and underserved communities. Training programs such as the Comprehensive Minority Biomedical Program (CMBP) and the Continuing Umbrella of Research Experiences (CURE), which target high-school through post-doctoral students through established researchers, work to increase the number of minority scientists in biomedical research and enhance the careers of those already in the field.

BREAST CANCER

Despite significant advances in detection, diagnosis, treatment, and prevention, breast cancer continues to have a devastating impact on American women. By the end of 2001, almost 192,200 women are expected to have been diagnosed with breast cancer and nearly 40,200 to have died of the disease. An estimated 2.17 million women in the United States are living with breast cancer today, and thousands of women continue to lose their lives to the disease each year. SEER data indicate that breast cancer is the leading type of new cancer cases among women and, after lung cancer, the second leading cause of cancer deaths in women.

The increase in breast cancer incidence that began in the 1990s continues today. Statistics from the NCI's SEER Program reveal that the incidence of breast cancer, although still increasing, has slowed dramatically since 1990. Overall, breast cancer mortality rates also have shown an encouraging downward trend, dropping 2.1% per year from 1990 to 1997. This trend suggests that improved breast cancer management, from early detection to treatment, is having a beneficial effect. Still, the improvements in numbers of new cases and deaths from breast cancer have been less pronounced in non-white women than for white women.

BIOLOGY AND GENETICS

Specimen Resources: The successful development of molecular diagnostics depends on the availability of tumor tissue specimens. The NCI Cooperative Human Tissue Network (CHTN) provides researchers with access to approximately 9,000 cases of formalin-fixed, paraffin-embedded breast cancer tissue samples with associated pathology and clinical data. These samples are particularly well suited to validation studies of diagnostic and prognostic markers. More information is available at http://www.cbctr.ims.nci.nih.gov. The NCI Clinical Trials Cooperative Groups have banked tumor specimens from a large number of uniformly treated cancer patients.

Molecular Profiling: The application of comprehensive molecular analysis technologies to the development of profiles of molecular changes in tumor specimens holds the promise of changing the practice of oncology. DNA array technology has recently been used to establish profiles of gene expression in a series of breast cancer specimens. The analysis results in an easily visualized clustering of specimens that have similar patterns of gene expression and provides a relative measure of the similarity of the expression patterns between any two specimens. Identification of clusters of genes that are expressed in different cell types or are associated with cell proliferation have demonstrated that this technology will allow exploration of potentially important interactions between different cell types in tumors.

Estrogen Receptors: Estrogens influence the growth, differentiation, and function of the human reproductive system and stimulate the proliferation and metastatic activity of nearly 40% of breast tumors. Because many breast tumors express estrogen receptors (ERs), and because this expression can affect prognosis as well as provide targets for therapy, cancer researchers are critically interested in the role of estrogens and ERs in breast cancer. For the past decade, researchers have believed that cells express only one type of ER. The recent discovery of a second ER, however, revealed that each of these two receptors, now referred to as ER-alpha and ER-beta, activate target genes differentially. Researchers are now pursuing clues about how each receptor actually activates target genes. Efforts with high potential significance include work on co-activators and repressors of ER.

BRCA1 and BRCA2 Gene Mutations: About 5% of the new cases of breast cancer that occur each year are related to heritable factors. Studies of women with a family history of breast cancer have revealed that alterations in two genes, BRCA1 and BRCA2, increase the risk of developing breast cancer.

Scientists know that BRCA1 and BRCA2 are tumor suppressor genes that, when working correctly, prevent some stage of tumor development. Investigators have gained insights into two major cancer-associated functions of BRCA1: 1) a deficiency in cell cycle check points and 2) amplification of centrosomes. Centrosomes are cellular structures involved in the distribution of genetic material during cell division. Abnormalities in centrosomes can therefore explain the most commonly observed genetic abnormalities in cancer cells-the presence of extra copies of chromosomes carrying oncogenes or the loss of chromosomes that harbor tumor suppressor genes. Further, BRCA1 and BRCA2 mutations appear in only a few inherited tumors-never in sporadic (noninherited) cancers and never in normal tissue-indicating that their function is highly specific. Beyond these facts, there is as yet little scientific consensus about how these two genes work.

One hypothesis is that BRCA1 and BRCA2 are "caretaker" genes; that is, they are responsible for ensuring that the cells in which they reside replicate appropriately. Mutation of a caretaker gene does not cause cancer directly but rather induces genetic instabilities that in turn lead to cancer-causing mutations in other genes. Scientists believe that such tumors will respond favorably to agents that induce the type of genomic damage that is normally detected or repaired by the particular caretaker gene involved. For example, mouse embryos that lack BRCA2 are unusually sensitive to radiation, implying that human tumor cells with defective copies of BRCA2 may also be unusually sensitive to radiation and that these tumors may therefore be highly amenable to radiation treatment.

Although women who have inherited a germline mutation in the BRCA1 gene have an increased risk of developing breast cancer over that of the general population, actual disease occurrence varies greatly among women with the BRCA1 mutation. This is because other genes, particularly those involved in endocrine signaling, are thought to modify this risk. For example, studies of the effects of repeat-length polymorphism found in exon 1 of the androgen receptor gene suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

RISK FACTORS

Genetic Factors: Research is underway to identify genetic changes that predispose to the development of breast cancer among families with breast, ovarian, and/or colon cancer. These studies will explore interactions between genes and between genes and the environment that may contribute to cancer risk among families participating in the Cooperative Family Registries for Cancer Studies (CFBCRS). Initiated in 1995, the CFBCRS now includes data from more than 5,000 families, providing researchers with biological and data resources needed to explore key questions about inherited mutations in cancer susceptibility genes. The registry also provides follow-up data on epidemiology, data on recurrence, and new morbidity and mortality in the participating families. Additional information on the CFRBCS can be found at http://www-dccps.ims.nci.nih.gov/CFRBCS.

The Cancer Genetics Network, a group of collaborative clinical centers of excellence in cancer genetics, will provide another venue for examining these issues. In addition, the network centers will participate in the development and testing of interventions to better prevent, detect, and treat breast cancer among individuals at high risk (including genetic risk). Located in several areas of the United States, the network centers will collaborate on a variety of studies of familial cancer and cancer susceptibility, including environmental exposures that may interact with susceptibility genes.

Diet: The incidence of breast cancer is substantially lower in Asian countries than in the United States. A possible explanation for this difference is that Asian women consume much greater amounts of soy-based foods than do American women. Isoflavonoids, which are present in soy foods, are structurally similar to estradiol, a mammalian estrogen. It has been hypothesized that isoflavonoids may influence the risk of breast cancer. Overnight urine samples collected from women participating in a cohort study in China were analyzed for major isoflavonoids. Levels of these isoflavonoids in urine were substantially lower in women who had been diagnosed with breast cancer than in control women. These results support the hypothesis that a high intake of soy foods may reduce the risk of breast cancer.

Other Lifestyle Factors: Physical activity, body mass index, and weight change are being intensively studied for their relationship to the risk of breast cancer. Multidisciplinary projects are attempting to assess how alcohol and tobacco use, physical activity, obesity, dietary factors, hormones, estrogen metabolism, and susceptibility factors may interact in the etiology of breast cancer. Methodologic research is assessing how best to measure physical activity during work and recreation, seasonally, and over women's life spans.

Hormones: Investigators recently evaluated the relationship between sex steroid hormone levels in plasma and the risk of breast cancer in postmenopausal women in a nested case-control study within the Nurses' Health Study. The researchers found statistically significant associations between the increased risk of breast cancer and circulating levels of the hormones estradiol, estrone sulfate, and dehydroepiandrosterone sulfate. These associations were substantially stronger among women who had never received hormone replacement therapy (HRT). Together with past epidemiologic and animal studies, these results strongly suggest a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.

Prolactin, a polypeptide hormone, is essential for the development of mammary glands and for lactation. Administration of exogenous prolactin enhances the rates at which mammary tumors develop in animals. In a recently completed nested case-control study within the Nurses' Health Study cohort, a significant positive association was observed between the levels of prolactin in plasma and the risk of postmenopausal breast cancer. This association was independent of plasma levels of sex steroids. It may be that the increase in prolactin levels associated with estrogen use and with certain medications (e.g., reserpine) have a role in the increased risk of breast cancer seen among women with long-term use of these compounds. The positive relationship observed between prolactin levels and breast cancer is similar in magnitude to that observed for plasma estrogens and warrants further, detailed evaluation.

Recently published data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial show that about one-quarter of women who use HRT that includes progestin and about 8% of those taking estrogen-only therapy have an increase in breast density on their mammograms. It is not known whether increased breast density due to HRT carries the same risk as having naturally dense breasts, but increased breast density from HRT does make it more difficult for a radiologist to read some mammograms. Studies have suggested that such a reduction could lead to about a 30% increase in follow-up mammographic studies and an increase in breast biopsies. One retrospective study showed that short-term cessation of HRT improves mammographic accuracy. This strategy may be useful for women undergoing screening mammography or in lieu of immediate biopsy for some women with inconclusive mammograms. Recent evidence suggests that women who have long-term exposure (more than 10 years) to HRT may have a slightly increased risk of developing breast cancer, but this is not known to be linked to the increases in breast density that may occur. HRT has also been studied in relation to breast cancer risk in research comparing use of estrogen-progestin with estrogen alone. This study used follow-up data from 46,000 women who participated in the Breast Cancer Detection Demonstration Project (BCDDP), a nationwide breast cancer screening program conducted between 1973 and 1980. Compared with non-users of HRT, the relative risk for breast cancer among women who had used hormones during the previous 4 years increased by 8% per year for estrogen-progestin therapy and by 1% for estrogen therapy alone. There was no increase in risk among women who had stopped either therapy for more than 4 years.

Environmental Factors: The NCI has a broad and wide-ranging research program of laboratory and epidemiologic investigations into the links between breast cancer and exposures to pesticides, air pollution, drinking water contaminants, electromagnetic and ionizing radiation, and lifestyle and other factors. Because environmental exposures are indirect, are experienced passively, and often occurred a long time in the past, it is difficult to quantify the long-term dose to any individual. A major thrust of current research work is focused on biomarker approaches (genetic, molecular, cellular, and tissue or organ specific) as one way to assess internal dose. Particular interest has been focused on identifying markers of cancer risk, for example, detecting and quantifying influential environmental exposures, as indicators of mechanisms relating exposures and cancer or as measurements of individual susceptibility to cancer. Research is being conducted to measure the estrogenicity of environmental chemical exposures to identify additional chemicals and mixtures to be brought under study in the future, and markers of exposure are being developed and validated.

Categories and specific examples of research currently supported include identification of geographic areas with increased breast cancer incidence, morbidity, and mortality and potential contributions of local environmental factors. Among these projects is an extensive breast cancer case-control study among residents of Long Island, New York, undertaken by the NCI with the National Institute of Environmental Health Sciences (NIEHS). The Long Island Breast Cancer Study Project (LIBCSP) is examining the possible association of breast cancer risk with exposures to contaminated drinking water; indoor and ambient air pollution, including pesticide levels in household dust; electromagnetic fields; and hazardous and municipal wastes. In 1999, NCI awarded a 5-year contract to develop a health-related geographic information system (GIS) for Long Island (http://www.healthgis-li.com). The prototype health-related GIS will provide researchers with a new tool to investigate relationships between breast cancer and the environment on Long Island and to estimate exposures to environmental contamination. More information on the LIBCSP, including descriptions of the ongoing studies, can be found at http://www.dccps.ims.nci.nih.gov/LIBCSP/index.html.

In addition, the NCI and the CDC are jointly following a group of farm families accidentally exposed to high levels of polybrominated biphenyls (PBBs) during the 1970s to look at a variety of health outcomes, including risk for breast cancer. Chemicals traditionally associated with agriculture (e.g., pesticides and fertilizers) can now be commonly found in urban areas. In collaboration with the NIEHS and the Environmental Protection Agency, the NCI launched in 1994 the nation's largest study of farmers and their families. The Agricultural Health Study has identified about 100,000 farmers and their spouses and children to assess exposures and cancer (and non-cancer) health outcomes.

Radiation: Ionizing radiation in high doses is a well-established risk factor for breast cancer. Current research focuses on the specific effects of diagnostic, therapeutic, and occupational exposure to ionizing radiation in established cohorts such as X-ray technologists, ataxia-telangiectasia carriers, and A-bomb survivors. Multidisciplinary investigations are focusing on genetic susceptibility to radiation carcinogenesis and the interactions of radiation dose,hormonal factors, and genetic factors. Scientists have found that women with scoliosis (abnormal curvature of the spine) who were exposed to multiple diagnostic X-rays during childhood and adolescence may be at increased risk of developing breast cancer. The researchers found that the risk of developing breast cancer increased significantly with the number of X-rays and the cumulative radiation dose.

Non-ionizing radiation (electromagnetic-field) exposure has been hypothesized to affect breast cancer risk through changes in melatonin levels that affect estrogen secretion. Current research is measuring electromagnetic-field exposure in several cohorts, including teachers in California, nurses in several areas of the United States, and women included in the Long Island Breast Cancer Study Project.

EARLY DETECTION AND DIAGNOSIS

Imaging Technologies: Important advances in imaging systems are being applied to the detection of breast cancer. The NCI is funding research on a variety of technologies for breast imaging, including digital mammography, elastography, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), a number of ultrasound techniques, positron emission tomography (PET), single-photon emission computed tomography (SPECT) using a number of compounds designed to look at molecular biological and metabolic characteristics, and optical technologies emphasizing the use of the near-infrared region of the spectrum.

Projects being funded include a multi-center, international clinical trial on the use of MRI in the detection of breast cancer. Nearly 700 patients have been accrued at 10 centers in this trial to test MRI as a tool to decrease the number of false-positive X-ray mammograms that lead to biopsy. The NCI is also funding a multi-center trial of breast MRI as a screening test for breast cancer in women at high risk for breast cancer. In 1999, the NCI initiated funding of a large, 5-year project combining the development of four of the above technologies, all of which will be tested in a group of interested women presenting for mammography. Ongoing research in 11 digital mammography projects includes X-ray source and digital detector development, image optimization and interpretation studies, and studies of impact and cost.

Digital mammography: One of the most promising research areas for improving early detection of breast cancer, digital mammography uses X-rays like conventional mammography, but data are collected on a computer instead of on film. This means that the image can be computer enhanced and specific areas magnified. Computer algorithms can screen digital mammograms, detecting suspicious areas that human review might miss. One such computer detection system has now been approved by the FDA. Extensive effort is required for the successful development, testing, and implementation of digital mammography displays and work station design for image interpretation. In 1999, the NCI released Program Announcements soliciting research applications to overcome problems with digital mammography design. The first digital mammography system was approved for clinical use, based on safety and effectiveness in clinical trials, by the FDA in March 2000.

Other diagnostic imaging initiatives: The NCI is supporting the American College of Radiology Imaging Network (ACRIN), a national, multi-institutional network for cooperative studies in diagnostic imaging. Studies in breast cancer form an important part of the research agenda of the network and are aided by collaborative arrangements with the clinical cooperative groups. In 2001, ACRIN will begin a large trial to compare digital mammography with conventional film mammography. Included will be 19 sites using digital mammography machines from four manufacturers. A total of 49,000 women will be recruited into the trial, the results of which are expected in about 3 years.

To speed the development of new imaging methods, the NCI has created the Small Animal Imaging Resource Program (SAIRP). Five centers are developing and applying a wide variety of functional, quantitative imaging modalities, and five additional centers will be added in 2001. Quantitating imaging data for small animals will lead the way to methods that can be applied in humans. Many initiatives link technology with research through partnerships with industry and through Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms.

Programs to Increase Mammography Use: Breast cancer is predominantly a disease of the elderly, who could significantly reduce their mortality rates with regular use of mammography. A recently released national telephone survey conducted by the NCI and the Health Care Financing Administration (HCFA) indicates that, although the rate of mammography screening among women ages 65 and older has increased by 25% since 1992, misconceptions about breast cancer risk and the potential benefit from regular breast cancer screening are prevalent among older women. The NCI and HCFA have formed a partnership to raise awareness about regular mammography screening and of the expanded mammography screening benefit for Medicare beneficiaries among women ages 65 and older. The partnership's efforts are expanding to increase the number of providers who refer female Medicare beneficiaries ages 65 and older for screening mammograms. The NCI and HCFA will work with professional medical organizations to increase awareness among providers and will develop materials that facilitate communication between providers and patients about mammography and breast cancer.

Sentinel Node Biopsy: Because metastatic cancer most often spreads first to sentinel lymph nodes, many axillary lymph nodes are usually dissected to assist in diagnosing the stage of disease. More than 80% of women who undergo a complete axillary dissection have at least one complication after surgery, including lymphedema (swelling in the arm caused by excess fluid buildup), numbness, persistent burning sensation, infection, and limited movement of the shoulder. Although research suggests that the sentinel nodes (one or a few lymph nodes) can be used to determine whether cancer has spread to other lymph nodes, it has yet to be determined what the impact of removing only the sentinel node will have on cancer control and survival. Two studies are now ongoing in which the effects of sentinel node biopsy are being compared with the standard practice of removing a much larger number of axillary lymph nodes. One of these studies is examining whether sentinel lymph node biopsy can replace axillary lymph node dissection in breast cancer patients with negative sentinel nodes. The second study will examine the same issue in women with positive sentinel nodes. Both study groups hope to learn whether long-term survival for patients who do not receive an axillary node dissection differs from that in patients who undergo a complete dissection. The studies will also compare the post-surgical side effects between the two groups.

PREVENTION

Chemoprevention: The growth of breast cancers is significantly affected by hormones. Several drugs that partially block the effects of the hormone estrogen on breast tissue are being studied for use as chemopreventive agents. The precedent-setting Breast Cancer Prevention Trial (BCPT) found that the drug tamoxifen, which has been successful in treating ER-positive breast cancer, decreases the risk of breast cancer in women who are at increased risk of developing the disease. Using data amassed through March 31, 1998, the BCPT showed a 49% reduction in the incidence of breast cancer among the high-risk participants who took tamoxifen. Women taking tamoxifen also had 50% fewer diagnoses of noninvasive breast cancer, such as ductal or lobular carcinoma in situ. Tamoxifen was associated with an increased risk of endometrial cancer, pulmonary embolism, and deep-vein thrombosis. Further analysis of the results of the trial showed that younger women at high risk of breast cancer are the most likely to benefit from tamoxifen because their breast cancer risk substantially outweighs the potential for adverse effects of the drug.

One of the largest breast cancer prevention studies ever undertaken, the Study of Tamoxifen and Raloxifene (STAR), is currently enrolling participants through more than 500 centers across the United States, Puerto Rico, and Canada. STAR is a study of the National Surgical Adjuvant Breast and Bowel Project, which is supported by the NCI. The study will determine whether the drug raloxifene, which is used for osteoporosis prevention and treatment, is as effective as tamoxifen in reducing the risk of breast cancer while comparing the long-term safety of both drugs. Raloxifene was shown to reduce the incidence of breast cancer in a large osteoporosis trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) study. Women taking raloxifene in studies of osteoporosis have also shown an increased chance of developing deep-vein thrombosis or pulmonary embolism, risks similar to those associated with tamoxifen. In these studies, raloxifene did not increase the risk of endometrial cancer. More information on STAR is available at http://cancertrials.nci.nih.gov/types/breast/prevention/star.

Prophylactic Surgery: Despite inconclusive scientific surveillance data on prophylactic mastectomy, some women who are at high risk for breast cancer make the difficult decision to have both breasts surgically removed. In one recently published study, researchers looked at the long-term outcomes of prophylactic mastectomy among women with a family history of breast cancer who had undergone the surgery at the Mayo Clinic between 1960 and 1993. In this study, prophylactic mastectomy was associated with a reduction in incidence of the disease of at least 90%.

Prophylactic removal of the ovaries to decrease the risk of ovarian cancer upon completion of a woman's childbearing has been recommended for women with an inherited risk of breast and ovarian cancer. In a study of women with BRCA1 mutations who had an inherited risk of breast and ovarian cancer, the incidence of breast cancer was compared in those who had undergone prophylactic oophorectomy with those who had not. Prophylactic oophorectomy was found to reduce the risk of breast cancer by about 40% for all women with BRCA1 mutations, and this risk further decreased over time after surgery.

TREATMENT

Adjuvant Therapy: Panelists in an NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer, held in November 2000, agreed that treatment with a combination of chemotherapy drugs improves survival and should be recommended for most women with localized breast cancer. Also recommended was hormonal therapy for women whose tumors are positive for ERs, regardless of these women's age or menopausal status, tumor size, or whether the cancer has spread to nearby lymph nodes. Five years of tamoxifen therapy is currently the standard adjuvant hormonal therapy. Women who have undergone mastectomy and who have four or more cancerous lymph nodes or an advanced primary tumor benefit from post-surgical radiation. It is unclear whether women with one to three cancerous lymph nodes benefit from radiation therapy, and this question should be tested in a randomized clinical trial. The panelsts' report is available at http://odp.od.nih.gov/consensus/cons/114/114_intro.htm.

About half of all women with early-stage breast cancer (i.e., disease that has not spread to one or more lymph nodes) have ER-negative tumorsand so do not respond to tamoxifen, which acts directly on ERs. A recent study found that these women receive the same benefit from 3 months of a combination chemotherapy regimen consisting of adriamycin plus cyclophosphamide as they do from 6 months of the more widely used regimen of cyclophosphamide, methotrexate, and fluorouracil. These results indicate that breast cancer patients who do not benefit from the drug tamoxifen can decrease the duration of their drug therapy without diminishing their chances for long-term survival.

Effectiveness of tamoxifen for black and white women: An analysis of data gathered in nine studies from the National Surgical Adjuvant Breast and Bowel Project on adjuvant tamoxifen for treatment of breast cancer showed that the drug is as effective for black women as for white women in reducing the occurrence of contralateral breast cancer. In addition, the drug does not cause more side effects in black women, as was originally suspected. This finding also means that black women who are at increased risk for breast cancer can also benefit from tamoxifen as preventive therapy.

Ductal carcinoma in situ: Ductal carcinoma in situ (DCIS) has been diagnosed with rapidly increasing frequency with the advent of modern mammography screening standards. Until the late 1980s, this lesion was treated routinely with mastectomy. However, two studies have transformed the paradigm for treating this disease. An earlier NSABP trial showed that lumpectomy and breast irradiation for early-stage breast cancer achieved survival that was comparable to that with mastectomy. This, along with results of a study of tamoxifen in the therapy of DCIS, indicate that lumpectomy, breast irradiation, and tamoxifen can substitute safely for mastectomy in the treatment of DCIS. Other studies have confirmed that tamoxifen-radiation therapy should remain the standard of care in patients with early stage breast cancers and that tamoxifen reduces the occurrence of contralateral breast cancer.

Effectiveness of shorter radiation treatment: Results of a new study have shown that reducing daily radiation therapy from 5 weeks to 3 weeks is equally effective in preventing cancer recurrence in women who have chosen breast conserving therapy. Shortened radiation schedules lessen the overall burden for patients in terms of personal costs, travel, and time off work, as well as for the health care system in reducing costs and freeing resources for use of more patients.

High-dose chemotherapy with blood cell transplant: Over the past 20 years, more than 15,000 women with breast cancer have been treated with high doses of chemotherapy followed by blood cell transplants, in which cells are removed from the patient before chemotherapy to replace bone marrow damaged by the chemotherapy. Results of two studies released in 1999 showed that this treatment is no more effective than standard chemotherapy for women with advanced or high-risk breast cancer. Results from two studies published in early 2000 support the conclusions of the earlier studies. These later studies were randomized trials, comparing patients who received the high-dose treatments with patients who received standard therapy. Several large, randomized trials are ongoing to determine the survival advantages of the high-dose regimen. The current recommendation is that women should receive high-dose chemotherapy with transplant only as part of a high-priority clinical trial so that they can be followed for several years after treatment.

Herceptin: Trastuzumab (Herceptin) received FDA approval in September 1998 for the treatment of metastatic breast tumors that overexpress the HER2/neu protein after early trials showed positive results. Phase III studies are now underway to explore whether Herceptin is also effective when used immediately after surgery in earlier-stage disease. These studies are comparing the effectiveness of combination chemotherapies alone or with Herceptin, are combining treatments with tamoxifen for ER-positive tumors, and are addressing concerns about possible cardiac toxicity of the drug.

Buserelin: Buserelin, a drug commonly used to treat prostate cancer, suppresses the ovarian production of estradiol. A recent study indicates that buserelin may prolong survival in premenopausal women with advanced breast cancer for an average of 1 year. ER-positive breast tumors are usually treated with tamoxifen to block estrogen production and as an alternative to removal of the ovaries. Women treated with tamoxifen often develop high levels of the sex hormone estradiol, which is thought to inhibit the action of tamoxifen or even to contribute to the recurrence of breast cancer.

Angiogenesis inhibitors: The study of compounds that block angiogenesis-the formation of new blood vessels-represents a promising new avenue of cancer research. About 20 such compounds are currently being tested in early Phase I and II clinical trials, many of which include breast cancer patients. The promise of angiogenesis inhibitors includes the fact that they are less likely than conventional chemotherapeutic agents to cause side effects, including bone marrow suppression, gastrointestinal symptoms, and hair loss. The possibility of drug resistance also appears to be less with these agents because they target normal endothelial cells. Anti-angiogenesis therapy may prove to be useful in combination with therapy aimed directly at tumor cells; early trials with such combinations are now underway.

Other Research: Other ongoing therapeutic research includes studies of gene therapy strategies that target key stages of the cell cycle such as programmed cell death by using adenoviral vectors to transfer specific genes; Chemoprotection, a process where bone marrow cells are exposed to a virus containing a drug resistance gene, thereby permitting the administration of both higher and a greater number of doses of drugs that are otherwise toxic to the bone marrow; and various types of immunotherapy designed to stimulate anti-tumor responses.

Treatment of Menopausal Symptoms in Breast Cancer Patients: Many women whose breast cancer is treated with chemotherapy experience severe menopausal symptoms as a result of chemotherapy-induced ovarian damage or prophylactic oophorectomy. Physicians are hesitant or unwilling to prescribe HRT for relief of menopausal symptoms, such as hot flashes, in these women because of concern for the possible risk of cancer recurrence. In a recent large, controlled clinical trial, the antidepressant venlafaxine (Effexor) was shown to substantially reduce hot flashes in a majority of the trial participants using half the dose prescribed for relief of depression. Antidepressants offer a new for control of menopausal symptoms for all women.

CERVICAL CANCER

Cervical cancer accounts for 6% of all malignancies in women. An estimated 12,900 cases of invasive cervical cancer are expected to be diagnosed in American women in 2001, with about 4,400 deaths from the disease. It is estimated that 90% of these cases could have been detected early through the use of the Pap test and that approximately one-third of eligible women are not having recommended Pap tests for screening cervical abnormalities. Throughout the world, the incidence of cervical cancer is a close second behind that of colorectal cancer as the leading cancers among women. In some developing countries, cervical cancer is the most common cancer and 400,000 new cases are diagnosed annually, predominantly among the economically disadvantaged in both developing and industrialized nations.

The rate of cervical cancer among all U.S. women is about 8 per 100,000. The disease is a particular concern, however, for minority and underserved populations in the United States. Through the Center to Reduce Cancer Health Disparities, the NCI is leading an initiative focused on the high rate of cervical cancer incidence and mortality in rural, economically distressed regions. These health disparities are of special concern in light of the fact that cervical cancer mortality declined by 45% between the periods 1972-1974 and 1992-1994 and its incidence declined by 43.3% from 1973 to 1995. Although the rate of death from cervical cancer among African Americans has declined more rapidly than that among whites, the African American death rate continues to be more than twice that of whites. The higher African American death rate may be due to the high number of cervical cancer deaths among older black women. The highest age-adjusted incidence of cervical occurs among Vietnamese women, followed by Alaska Native, Korean, and Hispanic women. Many of the racial and ethnic differences may be attributed to differences in known cervical risk factors, including long intervals since last Pap test and factors that increase the risk of infection with human papillomavirus (HPV).

The NCI will convene a Gynecologic Cancers Progress Review Group Roundtable in June 2001 to focus on cervical, ovarian, and endometrial cancers. The Progress Review Group includes 30 prominent members of the scientific, medical, industry, and advocacy communities who have been charged with outlining and prioritizing a national research agenda for gynecologic cancers. These experts will identify priority areas for research, using the NCI's current research program as a baseline. The final report of the Progress Review Group, scheduled to be released in late 2001, will include research priorities and the resources needed to achieve those priorities.

RISK FACTORS

Human Papillomavirus: Studies have shown that approximately 90% of cervical cancers and cervical hyperplasias are associated with HPV; primarily types 16, 18, 31, and 45. HPV type 16 is the virus type most commonly detected in tumors, accounting for 50% of cancers and their precursors, high-grade squamous intraepithelial lesions. Recent studies suggest that HPV-16 variants have various degrees of association with the development of cervical neoplasias. These findings suggest that HPV infection is the primary cause of cervical neoplasia and support the clinical applications of HPV DNA testing and primary prevention of cervical cancer by vaccination.

Co-Factors: Immunologic and other co-factors are the focus of a current, large NCI study in Costa Rica. Investigators have screened about 10,000 women to obtain data on the incidence and prevalence of HPV infection and the co-factors that increase the risk of cervical cancer. These researchers are also evaluating some new diagnostic technologies and are looking at co-factors that may work with HPV to promote carcinogenesis. These co-factors may include immune system functioning, smoking, nutritional factors, hormonal factors, and the presence of other sexually transmitted diseases.

Age: The risk of dying of cervical cancer increases with age. Rates of cervical carcinoma in situ (cervical cancer that has not invaded surrounding tissues) reach a peak in both black and white women between the ages of 20 and 30 years. The number of cases of invasive cervical cancer increases with age after age 25 in both white women and black women, but it increases strikingly with age only in black women.

Pap testing: Women who have never had a Pap test or who have not had one for several years have a higher-than-average risk of developing cervical cancer.

Sexual history: HPV is a sexually transmitted virus. Women who first had sexual intercourse at an early age or who have had many sexual partners have a higher-than-average risk of developing cervical cancer. Women whose male sexual partners have themselves had many sexual partners are also at increased risk, according to several studies.

Diethylstilbestrol: The drug diethylstilbestrol (DES) was administered to pregnant women in the United States and Europe between 1938 and the early 1970s to prevent miscarriage or premature delivery. DES has been linked to the development of clear cell adenocarcinoma of the vagina and cervix in exposed daughters. As many as 3 million women in the United States may have been exposed to DES in utero. The emphasis of current research is to provide continued follow-up to DES-exposed mothers, daughters, and sons and their offspring as they age and to identify any cancer or other health risks that may be found in these groups. Some studies have found that DES-exposed mothers have an increased risk of breast cancer.

In July 1999, the NCI, the NIH Office of Research on Women's Health, and several other Federal agencies convened a workshop entitled "DES Research Update 1999: Current Knowledge, Future Directions." This workshop provided an update on research as well as a platform for discussion of current and future needs and recommendations for addressing those needs. The report of the workshop is available at DES/index.html.

The NCI is providing funding to the CDC to develop a DES National Education Campaign. The campaign, which plans to release new materials in late 2001, focuses on increasing the awareness of health professionals and the general public about the health effects of DES exposure and the need for careful screening and follow-up.

SCREENING AND EARLY DETECTION

Pap Test Screening: Despite evidence that regular screening can prevent cervical cancer and save lives, many women still do not have regular Pap tests. Data from the 1994 National Health Interview Survey show that about one-fifth of women ages 18-64 had not had a Pap test in the preceding 3 years, and about half of women with newly diagnosed invasive cervical cancer had not had a Pap test in the past 5 years. The largest groups of unscreened populations include older women; the uninsured; ethnic minorities, especially Hispanics; elderly African-American women; and poor women, particularly those in rural areas.

The NCI has developed a campaign to heighten public awareness of the increased risk for cervical cancer among older women and the importance for these women to have regular Pap tests. Women aged 65 and older account for nearly 25% of all cervical cancer cases and 41% of cervical cancer deaths in the United States, but they have much lower screening rates than younger women.

HPV Testing: A recent NCI-supported study in Costa Rica indicates that testing for HPV DNA can accurately identify many precancerous changes in the cervix and may be a useful screening tool for cervical cancer in some populations. When compared with other methods, including the conventional Pap test, the HPV DNA screening test accurately detected a high proportion of the precancerous, high-grade lesions as well as all cases of cervical cancer in this population. The HPV test was more sensitive but less specific than conventional Pap testing.

HPV testing has recently been shown to be useful in managing diagnoses of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL). The ASCUS/LSIL Triage Study (ALTS), sponsored by the NCI and conducted at four major medical centers, was designed to help physicians and women decide what to do about ASCUS and LSIL Pap test results. Although most of these cases are mild abnormalities, some may progress to a precancerous condition or cancer. ALTS looked at three different ways to manage ASCUS and LSIL identified by Pap test: 1) women were referred for immediate colposcopy to identify abnormal tissue for biopsy and possible treatment; 2) women were followed closely with a repeat Pap test every 6 months and colposcopy and biopsy when repeat Pap tests suggested more severe abnormalities; 3) women were tested for HPV and those with positive results for HPV types associated with cancer were referred for colposcopy. HPV testing proved to be highly sensitive in detecting ASCUS lesions needing immediate attention. The test was determined to be 96% sensitive in triaging women with precancer or cancer to colposcopy. About 55% of women with ASCUS were HPV positive, and 10-20% of these women had precancer or cancer. The test thus had a positive predictive value of 10-20%. The negative predictive value was 99.5% in showing that women with a negative HPV test did not have precancer or cancer. In comparison, repeat thin-layer Pap tests were shown to be about 85% sensitive as a referral for colposcopy. The study found that the value of HPV testing in women with LSIL is limited because of the high prevalence (82.9%) of HPV infection in these women.

PREVENTION

HPV Vaccine Development: Recent efforts to prevent cervical cancer have focused on the development of a vaccine to prevent HPV infection. Several different vaccines are under development at centers around the world, three of which have reached human clinical trials. One of these vaccines, developed at the NCI, has been tested in a Phase I double-blind, placebo-controlled, dose escalation trial to evaluate its safety and immunogenicity. Recently published results show that vaccination with the HPV-16 L1 VLP vaccine is safe and stimulated production of HPV antibodies. A Phase II study will test the NCI vaccine in a larger group of women in the United States and Costa Rica.

TREATMENT

In early 1999, data from five large, randomized clinical trials carried out by the NCI's Clinical Trials Cooperative Groups showed that women with advanced cervical cancer who received chemotherapy with cisplatin concomitantly with radiation therapy lived longer and experienced fewer disease recurrences than those treated with radiation alone. Although the trials varied somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, all demonstrated significant survival benefit for the combined approach. Concurrent chemoradiation reduced the risk of death from cervical cancer by 30-50%. On the basis of these results, the NCI issued a clinical alert urging physicians to give strong consideration to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.

Other studies underway are comparing different kinds and combinations of chemotherapy drugs to include in the treatment of invasive cervical cancer. Investigators are also looking at the impact of both surgery and radiation therapy on quality of life and at ways to improve quality of life after treatment.

OVARIAN CANCER

Ovarian cancer has the highest mortality of all cancers of the female reproductive system. When detected early it is highly treatable. However, since it is often asymptomatic in its early stages and symptoms that do occur are rarely of the type that would alert most women or their caregivers, more than 70% of ovarian cancers are diagnosed at advanced stages of disease. When diagnosed and treated early at the localized stage, the 5-year survival rate is 95%, whereas the survival rates for regional and distant stages are 79% and 28% respectively. In 2001, approximately 23,400 women in the United States are expected to be diagnosed with ovarian cancer, and approximately 13,900 are expected to die of the disease.

In 1999, the NCI awarded funding for Specialized Program of Research Excellence (SPORE) grants to four institutions for research on ovarian cancer. These institutions are the Fred Hutchinson Cancer Research Center, the University of Texas M. D. Anderson Cancer Center, the Fox Chase Cancer Center, and the University of Alabama at Birmingham. SPORE grants support innovative, multidisciplinary translational research approaches that may have an immediate impact on improving cancer care and prevention. Laboratory and clinical scientists in the SPORE programs will work collaboratively to plan, design, and implement research programs that focus on translating basic research findings into improvements in prevention, earlier detection, diagnosis, and treatments for ovarian cancer. To facilitate this research, each SPORE develops and maintains specialized resources that benefit all scientists working on the specific cancer site, as well as SPORE scientists.

RISK FACTORS

The lifetime risk of ovarian cancer is 1.8%, and its annual incidence is about 61.8 per 100,000 women who reach ages 75-79. The causes of ovarian cancer are unclear. According to one theory, constant, uninterrupted ovulation increases the risk of ovarian cancer, which could explain why pregnancy, breast-feeding, and oral contraceptive use are associated with a decreased risk of ovarian cancer. Other theories speculate that increased pituitary gonadotropin levels contribute to an increased risk of the disease or that alterations in ovarian blood flow or the transtubal transportation of carcinogens may be involved in the development of ovarian cancer.

Inherited Risk Factors: Three inherited ovarian cancer susceptibility syndromes have been described: 1) familial site-specific ovarian cancer, 2) familial breast/ovarian cancer, and 3) Lynch II syndrome (combination of breast, ovarian, endometrial, gastrointestinal, and genitourinary cancers). It is believed that 5-10% of ovarian cancers are caused by inherited mutations in the BRCA1 or BRCA2 genes. The NCI has organized a working group on cancer genetics for women with BRCA1 and BRCA2 mutations. This group brings together representatives of the Cancer Family Registries and the Cancer Genetics Network with representatives of the Clinical Trials Cooperative Groups and the Society of Gynecologic Oncologists. The goal of the working group is to develop prospective cohort studies and clinical trials to help identify interventions that can reduce the risk of developing breast or ovarian cancer; to assist these women in making decisions on reproductive issues, such as child-bearing and the use of HRT; and to aid in delineating the contributions of environment, reproductive health, and genetics to the risk of developing cancer.

Other Risk Factors: Risk factors for ovarian cancer other than family history include age over 50, never having had children, a history of breast or colon cancer, use of fertility drugs (the possible association is under study), use of talc in the genital area for many years, and the use of postmenopausal HRT. Some studies of dietary differences between industrialized and non-industrialized nations show an increased risk for ovarian cancer to be associated with the consumption of meat and animal fat. In a population-based, case-control study, consumption of saturated fats was observed to be associated with an increased risk for ovarian cancer and consumption of vegetable fiber was associated with a decreased risk. Other studies looking at disease associations with serum cholesterol, serum selenium, or consumption of milk have been inconclusive.

SCREENING AND EARLY DETECTION

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Ovarian cancers are part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial, which is investigating whether certain screening tests will reduce the number of deaths from these cancers. Screening for ovarian cancer includes a physical examination of the ovaries, a blood test for the tumor marker CA-125, and transvaginal ultrasound. The trial will recruit approximately 152,000 healthy men and women, ages 55-74, as participants. As of September 30, 2000, recruitment was completed at 8 of the 10 screening centers, and the remaining centers will complete recruitment by the end of September 2001. Information on the PLCO trial is available at http://dcp.nci.nih.gov/plco.

Early Detection Research Network: The NCI has initiated the Early Detection Research Network (EDRN), a multi-institutional network to develop sensitive and specific biomarkers for the early detection of cancer. One component of this network is a collaborative group of research centers that will work together to identify better markers for ovarian cancer. More information on the EDRN can be found at http://edrn.nci.nih.gov.

Cancer Genome Anatomy Project: The CGAP is an interdisciplinary program to establish information, reagents, and technological tools needed to decipher the molecular anatomy of a cancer cell. The overarching purpose of the CGAP is the comprehensive molecular characterization of normal, precancerous, and malignant cells. Molecular markers for the detection of ovarian cancer is a high priority of this gene discovery effort. Ovarian cDNA libraries in the CGAP database now number 21; of these, 8 are from normal ovarian tissue, 3 are from precancerous tissue, and 10 are from ovarian cancer. To date, about 40,000 sequence reads from ovarian libraries have been performed. These sequencing efforts have identified 186 ovarian-specific and 523 ovarian-unique genes.

PREVENTION

Oral Contraceptives: Several studies have shown that the risk of ovarian cancer is decreased by 40-50% in women who take oral contraceptives. This effect increases with time, ranging from a 10-12% decrease in risk after 1 year of use to a 50% decrease after 5 years. The protective effect persists for 10-15 years after oral contraceptive use is discontinued. The use of oral contraceptives was found to be protective for women regardless of whether they had children, a family history of ovarian cancer, or hereditary ovarian cancer syndrome.

Tubal Sterilization: Results from the Nurses' Health Study showed a 33% decrease in the risk of ovarian cancer in women who had tubal sterilization. Also found was a weaker but statistically significant decrease in risk among women who had undergone simple hysterectomy.

Prophylactic Oophorectomy: In retrospective studies, prophylactic oophorectomy appeared to decrease the risk of ovarian cancer, perhaps by as much as prophylactic mastectomy decreases the risk of breast cancer. Prospective mutation-specific studies, however, are needed to more clearly define the protection associated with prophylactic oophorectomy. Even with surgery, women still appear to be at risk for primary peritoneal cancer. Potential benefits must be weighed against the risk of surgery and premature menopause.

TREATMENT

New Drug Strategies: The use of newer drug combinations holds promise in overcoming the resistance to platinum-based drugs that develops in many ovarian cancers after initial treatment. Each of the new drugs oxaliplatin, epirubicin, liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, and vinorelbine has produced a response in ovarian cancer patients when used alone and are now being tested in two- and three-drug combinations. Also promising in early studies is the use of a second, or consolidation, round of standard-dose chemotherapy for patients whose tumors have responded well to the first round. Further study of consolidation with a combination of drugs that includes paclitaxel has been proposed. Other innovative approaches to the treatment of advanced ovarian cancer are in development or early trials. These include therapeutic vaccines, gene therapy, and anti-angiogenic agents.

Intraperitoneal Therapy: Intraperitoneal therapy entails the delivery of drugs directly to the abdominal cavity and its lining (peritoneum), the locations to which most ovarian cancers first metastasize. This strategy has been used for some time without being fully studied. Phase III trials of intraperitoneal therapy have been undertaken with various combinations of drugs, but the results have not shown clear-cut benefits over traditional chemotherapy. Several studies of combination regimens are currently under way.

High-Dose Chemotherapy with Stem Cell Transplant: High-dose chemotherapy with stem cell transplant is a rigorous therapy in which stem cell transplantation is used to restore bone marrow that has been destroyed by high doses of chemotherapeutic drugs. There is some evidence that relapsed patients who are sensitive to platinum-based drugs and have only small tumors after surgery may benefit from transplant. Further Phase III trials are needed to evaluate the treatment effectiveness of high-dose chemotherapy against its risks.

Fertility-Sparing Surgery: For women whose ovarian cancer has metastasized, hysterectomy and bilateral oophorectomy is usually unavoidable. Recent studies indicate that women diagnosed with early-stage ovarian cancer that involves only one ovary may have the option of preserving fertility by having only the affected ovary removed. In the studies, women who had undergone fertility-sparing surgery almost always resumed menstruation. Cancer recurred in fewer of the women who had fertility-sparing surgery than in those who had radical surgery. Survival times between the two groups were also nearly equal.

UTERINE CANCER

Cancer of the corpus uteri, or endometrium, is the fourth most common cancer among women in the United States. An estimated 38,300 American women will be diagnosed with uterine cancer in 2001, and approximately 6,600 American women will die from the disease. The incidence of endometrial cancer has fallen by over 26% in the past two decades, but the number of deaths per year from endometrial cancer has more than doubled in the past decade, due mainly to an increasing aging population.

RISK FACTORS

An increased risk for endometrial cancer has been associated with diabetes, cigarette smoking, and lack of physical activity, but possible mechanisms remain obscure. The predominant risk factor for this cancer is the use of exogenous menopausal estrogens such as those included in HRT. When menopausal estrogens are taken with progesterone, the elevation in risk is greatly reduced. Tamoxifen, used for the treatment of breast cancer and for prevention of breast cancer in high-risk individuals, appears to have estrogen-like effects on the uterus and may also be associated with an increased risk of endometrial cancer. Apart from these risk factors, the epidemiology of endometrial cancer is not well defined.

Understanding disparities in incidence and mortality for endometrial cancer is a high priority of the NCI. Age-adjusted mortality rates from endometrial cancers in the United States are highest among Hawaiian women, followed by black women. Lower incidence-to-mortality ratios among these women suggest that access to care may be a more acute problem for many.

BIOLOGY

Efforts are under way to better understand the pathogenesis and progression of both sporadic and hereditary endometrial cancers through the analysis of genetic alterations.

Microsatellite instability: Roughly 20% of endometrial cancers demonstrate a phenomenon called microsatellite instability, which is the abnormal expansion or contraction of repeated small sequences of DNA. Microsatellite instability is a common feature of hereditary nonpolyposis colorectal cancer (HNPCC); among HNPCC families, endometrial cancers are the second most common tumors. Findings of recent studies are helping scientists to understand the initiation of tumors through methylation, a primary cause of microsatellite instability in endometrial tumors, and to distinguish pathways of endometrial cancer development. Also recently evaluated were microsatellite instability and mutations of the gene PTEN in complex atypical hyperplasia (CAH), the precursor to endometrial cancer. The results of these studies suggest that mutation of PTEN is an early event in the development of endometrial cancer and may precede the development of microsatellite instability in some cases. These important insights into the initiation of endometrial cancer may help in the development of targeted therapies that will benefit patients with endometrial cancer.

Tumor suppressor genes: The NCI is also supporting efforts to isolate a novel tumor suppressor gene that is involved in the development of uterine papillary serous carcinoma, the most aggressive type of endometrial cancer. The research has identified a specific mutation in approximately 65% of USPCs and is closing in on the precise location of that gene. Cloning the gene involved in the deletion could contribute to an understanding of the mechanism of endometrial cancer development and potentially provide a marker to evaluate prognosis.

TREATMENT

The NCI-sponsored Clinical Trials Cooperative Groups, particularly the Gynecologic Oncology Group, continue to work to develop more effective therapies for women with endometrial cancer. The NCI is currently sponsoring a number of clinical trials for endometrial cancer, including four Phase III trials that are testing the treatments closest to clinical practice. Through the Gynecologic Cancer Intergroup, timely completion of Phase III trials will help to identify active treatments for this disease.

In May 2000, the NCI sponsored the workshop "Translational Research in Gynecologic Cancers." Participants included researchers across all of the relevant scientific disciplines. Issues discussed included the molecular determinants and markers in endometrial, cervical, and ovarian cancers and how knowledge and further research can be applied to the treatment of these diseases.

LUNG CANCER

Lung cancer is the leading cause of cancer death for men and women in the United States and claims the lives of an estimated 157,400 people in this country each year. It is estimated that lung cancer will affect 78,800 women in 2001, among whom mortality will be about 90%. Since 1987, more women have died each year of lung cancer than of breast cancer, which until that year had been the major cause of cancer death in women for more than 40 years. Although the current incidence of lung cancer among women is remarkably high, the rate of increase has begun to slow in recent years. The average annual rate of invasive lung and bronchus cancer among U.S. women in 2000 was 42.8 per 100,000. High lung cancer mortality rates reflect our limited ability to detect lung cancer at an early and potentially more curable stage. Through the use of available detection methods, most people are diagnosed in advanced stages of the disease, and only slightly more than 12% survive for 5 years. Survival improves dramatically-to 70%-when the disease is identified and treated early.

TRANSDISCIPLINARY TOBACCO USE RESEARCH CENTERS

Launched in 1999 under the joint sponsorship of the NCI, the National Institute on Drug Abuse, and the Robert Wood Johnson Foundation, Transdisciplinary Tobacco Use Research Centers (TTURCs) are helping to provide the needed infrastructure for tobacco research across many disciplines. TTURC researchers are tackling a wide range of topics, including genetic susceptibility, animal models of behavior, sociocultural factors, innovative treatments, and research on health care policy and the bioethical implications of tobacco control. The Centers will accelerate the development of interventions to control tobacco use, speed the transfer of these approaches to communities nationwide, and train a new generation of tobacco control researchers.

RISK FACTORS

Smoking: Smoking is known to be the most significant risk factor for lung cancer. Lung cancer mortality is about 13 times higher among current female smokers than among women who have never smoked. Former smokers retain a heightened cancer risk for the remainder of their lives. Despite these facts, many women continue to smoke and many young girls start smoking. Among women ages 18 and older, the prevalence of smoking declined from 1991 to 1995 for all racial and ethnic groups except Native American women. Between 1983 and 1995, smoking prevalence among college graduates decreased from 21% to 14%, but the decrease was less-from 41% to 36%-among adults with education below high school level.

The percentage of high school students who frequently smoke increased for all racial, ethnic, and gender groups (with the exception of African American females) during this period. Due to the addictive nature of nicotine and the dramatic effect of smoking on health, reports of increased smoking among high school students are particularly disconcerting. Recent reports indicate that smoking rates for high school males were 35.4% in 1995, 37.7% in 1997, and to 34.7% in 1999. Smoking rates for high school females were 34.3% in 1995, 34.7% in 1997, and 34.9% in 1999. The NCI, with other NIH Institutes, issued a recent Request for Applications on the prevention and cessation of tobacco use by children and youth in order to reduce the national prevalence of tobacco use and accompanying tobacco-related disease rates and economic costs.

Nicotine Addiction: Several groups of scientists continue to investigate whether a genetic susceptibility may exist for smoking, accounting for a person's starting to smoke or inability to stop smoking. These scientists have found that variations in the genes that regulate the actions of dopamine (a neurotransmitter in the brain) may influence smoking behavior. The regulating effect of nicotine on dopamine can induce a feeling of pleasure in smokers. Consequently, individuals with depression, attention deficit disorder, and eating disorders commonly "self-medicate" with nicotine. Greater knowledge of how these genes influence nicotine dependency and whether there are differences between men and women promises to provide important clues about how some people become addicted to tobacco and how we can help people stop using tobacco.

Two related NCI-sponsored studies further clarified the interaction of dopamine receptors and nicotine addiction. In one study, investigators showed that some people carry a specific variation in their dopamine receptor gene and were less likely to be smokers, or, if they smoked, were less likely to become addicted. They were also less likely to have started smoking before age 16. The results suggest that if addiction is partially a function of the complex interplay of genes and other factors, a better understanding of the genetic basis for smoking can lead to improved treatments for nicotine addiction. In the second study, scientists demonstrated that variations in the two genes that regulate dopamine are related to the age at which a person started smoking, the likelihood of being a current smoker, and the length of periods of smoking abstinence. This information suggests that it is possible to develop new drug therapies targeted to helping people stop using tobacco.

Environment: Each year, about 3,000 nonsmoking adults die of lung cancer as a result of breathing the smoke of others' cigarettes. Recent epidemiologic studies of nonsmoking women exposed to tobacco smoke in the home estimate that there is about a 20% higher excess risk for lung cancer in these women than in unexposed women. In November 1999, the NCI released the most comprehensive report on the health risks of secondhand smoke ever conducted. The monograph, "Health Effects of Exposure to Environmental Tobacco Smoke: The Report of the California Environmental Protection Agency," links environmental tobacco smoke not only to lung cancer but also heart disease, sudden infant death syndrome, nasal sinus cancer, and a host of other diseases in both adults and children. The monograph is available at http://rex.nci.nih.gov/NCI_MONOGRAPHS/MONO10/MONO10.HTM. According to current estimates, 6,000-36,000 deaths may be attributable to indoor exposure to radon in the United States. Direct information on the risk from exposure to indoor radon has been obtained from case-control studies, but these studies have yielded variable results.

Genetic Epidemiology of Lung Cancer and Smoking Study: To advance our understanding of genetic and environmental interactions that influence smoking behavior and lung cancer in particular, NCI will support a study on the genetic epidemiology of lung cancer and smoking. This interdisciplinary case-control study will explore how tobacco and genes influence both lung cancer and smoking by incorporating the study of siblings and an extensive biospecimen collection.

SCREENING AND DETECTION

The NCI has recruited 3,600 current and former smokers for the Lung Screening Study, a year-long, $3 million study of spiral computed tomography (CT) scans, promising but unproven technology for lung cancer screening. Researchers will compare the lung cancer detection rate of spiral CT scans with chest X-ray, measure how much and what kind of medical follow-up is needed for positive or ambiguous results, and track how frequently participants receive spiral CT scans outside of the study. The study will gauge the feasibility of a larger, longer study designed to determine whether the scans save lives. To obtain results in a relatively short time frame, the study builds on the scientific infrastructure of the 150,000-participant PLCO trial, launched by NCI in 1992. The PLCO is evaluating screening strategies for multiple smoking-related cancers and for colon polyps, a precancerous condition related to tobacco use.

PREVENTION AND CONTROL

NCI has identified "Research on Tobacco and Tobacco-Related Cancers" as one of its three new "Extraordinary Opportunities for Investment" in NCI's budget proposal for fiscal year 2002 (http://plan2002.cancer.gov). This Extraordinary Opportunity is intended to focus efforts and increase resources that could produce dramatic progress toward reducing the burden of cancer. It will result in new grant or contract awards; collaborative efforts with other NIH Institutes, other federal agencies, or private-sector entities; and new or expanded scientific programs within the NCI, bringing the NCI to a new era in cancer prevention and care.

Youth Prevention and Cessation Research: To further understand youth tobacco use and addiction, the NCI, in collaboration with other NIH Institutes, is supporting research on the prevention and cessation of smoking among youths. This research includes projects on the prevention of adolescent tobacco use, experimentation related to the onset of regular tobacco use, dependence and withdrawal, and cessation and treatment of tobacco use.

Studies on Tobacco Use and Addiction in Women: The number of tobacco-related deaths among U.S. women continues to rise. NCI is supporting several studies on tobacco use and addiction in women. Studies on reducing tobacco use by pregnant women are focused on helping low-income women quit, testing the ability of women's partners to assist them in quitting, and preventing relapse after delivery. Another study examines the relationship between smoking and major depressive disorder, a problem that disproportionately affects women. The NCI also is funding a major study of African American women's health that includes an examination of smoking behavior.

Efficacy of Exercise as an Aid for Smoking Cessation: Researchers at the Miriam Hospital and Brown University School of Medicine studied whether sedentary female smokers in a behavioral smoking cessation program would benefit from vigorous exercise. This study demonstrates that vigorous exercise, used in conjunction with a comprehensive cognitive-behavioral smoking cessation program, leads to improved rates of smoking abstinence.

Evaluating Innovative Tobacco Prevention and Control Programs: In an effort to learn how best to design and conduct state and community tobacco control programs, NCI is supporting 12 new research projects on innovative tobacco prevention and control interventions at the community, state, or multi-state level. Questions being addressed concern the impact of media campaigns on tobacco use behaviors, readiness to quit, attitudes toward tobacco advertising, and how to tailor media and policy interventions to influence high-risk groups.

Monitoring Progress in Tobacco Control: The NCI is working with public and private partners to build a comprehensive and integrated surveillance system to monitor tobacco control progress at the local, regional, and national levels. Through the Tobacco Use Supplement to the Current Population Surveys, final data from the 1990s was made available by the Census Bureau in Fall 2000 as a public-use data resource. The NCI will provide supplements to existing tobacco control grants to encourage researchers to analyze these data. The Institute is also beginning pilot work to determine the best approach to creating a public-use research resource of regional, state, and local tobacco-related policy and legislation to expand the capacity to assess the effect of various factors on the progress of regional and local tobacco control programs.

Communicating Tobacco Control Information: Because effective communication and information dissemination about emerging public health issues in smoking and tobacco control are critical to reducing adult and youth tobacco use, NCI established the Smoking and Tobacco Control Monograph series in 1991 (http://rex.nci.nih.gov/NCI_MONOGRAPHS/MONO10/MONO10.HTM). Recent data from the Tobacco Use Supplement to the Current Population Surveys have been used extensively in this series, for example, in Changing Adolescent Smoking Behavior, Cigars: Health Effects and Trends, and State and Local Legislative Action to Reduce Tobacco Use. Data from the Cigar monograph were used to support the June 2000 Federal Trade Commission's requirement that the seven U.S. cigar companies include warnings about significant adverse health risks of cigar use in their advertising and packaging.

COLORECTAL CANCER

The incidence of colorectal cancer in both women and men has declined in recent years. Nevertheless, it is estimated that 68,100 women in the United States will be diagnosed with cancer of the colon or rectum in 2001 and an estimated 29,000 women will die of the disease by the end of the year. Colorectal cancer is the third leading cause of cancer death among women in the United States.

In January 2000, the NCI convened the Colorectal Cancer Progress Review Group. The goal of the Progress Review Group was to develop a national research agenda for colorectal cancer research, including both the top research priorities and the resources needed to meet those priorities. The Progress Review Group presented their report to the NCI in April 2000. The complete report, Conquering Colorectal Cancer: A Blueprint for the Future is available at http://prg.nci.nih.gov/colorectal/finalreport.html.

BIOLOGY

A growing body of evidence suggests that hypermethylation of CpG islands (the addition of methyl groups to stretches of DNA where the C and G nucleotide pairing is repeated) can lead to gene inactivation in colon cancer and other tumor types. Methylation of CpG islands results in the silencing of several genes known to be involved in tumor initiation and progression and of genes involved in DNA repair. Using a new technology known as methylated CpG island amplification, which enables researchers to analyze simultaneously many genes that have undergone methylation, researchers have identified 30 methylation sites, seven of which are seen only in colon cancers and often in early-stage tumors. These seven sites identified a new subset, or phenotype, of colon tumors, known as the CpG island methylator phenotype (CIMP). It was noted that all of the CIMP colon tumors also had microsatellite instability due to the methylation of the DNA repair gene hMLH1. The discovery of this important connection between gene methylation and microsatellite instability is helping scientists to understand the initiation of tumors through methylation and to distinguish the pathways by which colorectal cancer develops sporadically. These important insights may help in the development of targeted therapies that will benefit patients with CIMP colon tumors.

RISK FACTORS

Diet and Exercise: The role of diet and exercise in the etiology of colorectal cancer remains unclear. Epidemiologic, experimental (animal), and clinical investigations suggest that diets high in total fat, protein, calories, and alcohol and low in calcium and dietary fiber, particularly that derived from vegetables, are associated with an increased incidence of colorectal cancer. Although positive associations with meat consumption or with fat intake frequently have been found, the results have not always achieved statistical significance. Most animal and epidemiologic studies show a protective effect of dietary fiber on colon carcinogenesis; however, investigators in the recently completed Polyp Prevention Trial found no evidence that adopting a low-fat, high-fiber, fruit and vegetable-enriched eating plan reduces the recurrence of colorectal polyps. Polyps are frequently precursors to colorectal cancer. Alcohol consumption and a sedentary lifestyle have been associated in some, but not all, studies with an increased risk of colorectal cancer.

Polyp Biomarkers Study: In collaboration with the Veterans Administration (VA), the NCI is establishing a biological specimen bank within an ongoing VA Cooperative Study. The study examines characteristics of and risk factors for the presence of large and small polyps; the new bank will permit the examination of several nutritional and genetic hypotheses that have a bearing on colorectal neoplasia.

Cooperative Family Registry for Colorectal Cancer Studies: The NCI currently supports six primary registries of familial colon cancer located throughout the world. These registries, whose first field studies were conducted in 1998, serve several purposes that are critical to the future success of research on inherited colon cancer. They assemble and maintain comprehensive lists of families with histories of colon cancer, including familial adenomatous polyposis syndromes and HNPCC. Detailed information is collected about a variety of factors, including race and ethnicity, diet, and lifestyle. The registries have a bank of blood samples and tumor biopsies from family members that can be used for research purposes.

SCREENING

Cancer Screening Practices: The 2000 Annual Report to the Nation on the Status of Cancer, 1993-1997 contained a special section on colorectal cancer. The use of screening tests for colorectal cancer was analyzed with information from the National Health Interview Survey and the Behavioral Risk Factor Surveillance System (BRFSS). The BRFSS showed that 20% of people aged 50 and older had had a fecal occult blood test in the year preceding the survey and 31% had had a sigmoidoscopy or proctoscopy in the past 5 years. Despite the low use of screening tests, incidence rates have declined since 1985 and the results of the National Health Interview Survey indicate gradual and modest increases in screening between 1987 and 1998. Reported use of proctosigmoidoscopy for people over age 50 increased from 24% to 38% during this period. New efforts are under way to increase awareness of screening benefits and treatment for colon cancer, including the CDC-led, broad-based educational campaign Screen for Life.

The NCI has launched a study to understand how screening for colorectal cancer is being conducted in the United States and to help identify barriers to screening and appropriate follow-up. Investigators from the NCI, CDC, and HCFA are collaborating to gather, for the first time, national data on colorectal screening practices. The study is designed to obtain nationally representative data on the physician and health system factors that may affect the use of screening and diagnostic follow-up related to early detection of colorectal cancer in community practice. It will assess physicians' knowledge, attitudes, and practice patterns, as well as health plan guidelines for providing or promoting colorectal screening. The NCI also has a formal working relationship with the CDC on colorectal cancer screening awareness programs.

Hereditary Nonpolyposis Colon Cancer: HNPCC is the most common form of inherited colon cancer, accounting for about 9,000 cases each year and affecting about 1 in 200 men and women. The high risk of colon cancer in persons who are genetically predisposed to HNPCC may be reduced by regular colonoscopic examination and removal of premalignant polyps. Although genetic testing for predisposition to HNPCC is available, an NCI-supported study found that a relatively small proportion of HNPCC family members are likely to use it. Barriers to testing include less formal education and symptoms of depression. Additional research is needed to explore these findings in different clinical settings and culturally diverse populations.

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: The PLCO trial is a large-scale study to determine whether certain screening tests will reduce the number of deaths from certain cancers. Subjects receive either the screening tests or routine care. For colorectal cancer, men and women are screened with flexible sigmoidoscopy.

PREVENTION

NSAIDs: The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and prevention of colorectal cancer is significant. Animal and human studies have documented a protective effect of NSAIDs, including piroxicam, sulindac, and aspirin. NSAIDs were found to inhibit chemically induced adenomas and early carcinomas of the colon in mice and to reduce the risk of colorectal cancer by 40-50% in humans. Before NSAIDs may be used to prevent or treat colorectal cancer, further clinical trials in humans are needed to define the optimal dose and drug.

TREATMENT

Adjuvant Therapy: Prior research has shown that, in patients with advanced colorectal cancer, treatment with the anti-cancer drugs 5-fluorouracil (5-FU) and levamisole after surgery leads to a 33% reduction in mortality over surgery alone. Armed with this finding, NCI-supported researchers are now working to identify other adjuvant treatment regimens that may be even more powerful in combating colorectal cancer. Trials of 5-FU, levamisole, and leucovorin have shown particular promise. Researchers have found that adjuvant treatment with 5-FU and leucovorin is as effective as the 5-FU-levamisole combination and requires a considerably shorter treatment regimen. It appears, however, that treatment with the three drugs together does not improve outcome.

Cooperative Colorectal Cancer Combination Chemotherapy Clinical (6C) Trial: Two of the most promising new drugs for the treatment of metastatic colorectal cancer, CPT-11 and oxaliplatin, are being tested in medical centers throughout the United States and Canada. The 6C Trial will enroll 1,700 patients to evaluate the drugs as initial therapy for advanced colorectal cancer. The drugs will be tested in combination with each other and with other drugs and compared with current standard treatments for colorectal cancer.

AIDS

PREVALENCE

AIDS and HIV infection continue to be major public health concerns, despite an overall decline in incidence of new AIDS cases since 1994. The CDC estimates that 800,000 to 900,000 U.S. residents are currently living with HIV infection, one-third of whom are unaware of their infection. Approximately 40,000 new HIV infections occur each year in the United States; about 70% of these are among men and 30% are among women. Of these newly infected people, half are younger than 25 years of age. As of June 2000, 753,907 cases of AIDS had been reported to the CDC since the beginning of the AIDS epidemic. From 1985 to 1999, the proportion of AIDS cases reported in adult and adolescent women in the United States increased from 7% to 23%.

BIOLOGY

AIDS-Associated Malignancies: Malignancies occur in more than 30% of patients living with AIDS. These include Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, cervical cancer, and anal cancer. Although Kaposi's sarcoma is extremely rare among women, non-Hodgkin's lymphoma currently ranks sixth in overall female cancer incidence and mortality. Furthermore, the risk of cervical neoplasia is five times higher in women with HIV infection than in uninfected women, due to the extraordinarily high prevalence of oncogenic HPV infection among HIV-seropositive women.

In 1996, the NCI created the AIDS-Related Malignancies Working Group to provide a national scientific forum to identify research opportunities and provide recommendations on research priorities and resource needs and how best to address these opportunities across the range of issues in AIDS-related malignancies. By design, this group represents a spectrum of disciplines working in relevant areas or directly with AIDS malignancies. Each year, the AIDS-Related Malignancies Working Group publishes a handbook that provides an accessible and comprehensive listing of the intramural and extramural clinical and laboratory AIDS research resources that receive NCI funding.

To further facilitate research on AIDS-associated malignancies, the NCI created the AIDS-Associated Malignancies Clinical (AMC) Trials Consortium and the AIDS Malignancy Bank (AMB) database. The consortium unites clinical investigators at respected medical institutions throughout the United States to conduct research on AIDS-associated malignancies. The database provides researchers with access to tissue specimens and clinical data from patients. More information regarding the AMC and AMB can be found at http://www.amc.uab.edu.

TREATMENT

Thalidomide: Although the incidence of (KS) has declined, it is the most common cancer in patients infected with HIV. Because these tumors depend heavily on angiogenesis (the development of new blood vessels) to foster their growth, anti-angiogenesis therapies may be particularly effective against this cancer. A recent trial of thalidomide in patients with AIDS-related KS showed shrinkage of tumors in nearly half of the cases. In addition to suggesting an effective new treatment for KS, this study is one of the first to establish that an anti-angiogenic drug can cause remissions in an established tumor.

HIV Microbicides: The development of an effective anti-HIV topical microbicide, in particular a female-controlled vaginal microbicide, has been deemed an urgent global priority by numerous international agencies. NCI-supported researchers have discovered a unique protein, cyanovirin-N (CV-N), that inactivates several strains of HIV, including those involved in sexual transmission, and also blocks cell-to-cell transmission of the virus. If toxicity testing of CV-N in humans is successful, it has the potential to be developed into an effective topical preventive ointment.

Requests for Applications (RFAs) and Program Announcements (PAs) Relevant to Women's Health, FY 1999-2000

RFA CA-98-025
Breast Cancer Surveillance Consortium Expansion
The Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute (NCI), invited applications from domestic institutions for cooperative agreements to support collaborative research within the Breast Cancer Surveillance Consortium (BCSC), established by the Cancer Surveillance Research Program (CSRP) in 1994.

RFA CA-98-029 (NCI, National Institute on Drug Abuse)
Transdisciplinary Tobacco Use Research Centers
The intent of this initiative is to provide support for the creation of Transdisciplinary Tobacco Use Research Centers (TTURCs), which will develop cross-disciplinary research programs in basic through applied sciences focused on understanding all aspects of addiction to nicotine and its health effects.

RFA CA-99-002 (NCI, DC)
Planning Grants: In Vivo Cellular and Molecular Imaging Centers (PRE-ICMICs)
RFA CA-99-004 (NCI, DC)
In Vivo Cellular and Molecular Imaging Centers
The Diagnostic Imaging Program invited applications for centers and for planning grants that lead to the establishment of In Vivo Cellular and Molecular Imaging Centers. These initiatives are designed to capitalize on the extraordinary opportunity for studying cancer non-invasively, and in many cases, quantitatively due to recent advances in molecular imaging modalities and molecular and cellular biology.

RFA CA-99-003
Special Populations Networks for Cancer Awareness Research and Training
The major goal of this initiative is to establish a robust and sustainable infrastructure to promote cancer awareness within minority and medically underserved communities and to launch from these more research and cancer control activities aimed at specific population subgroups.

RFA CA-99-007
The Early Detection Research Network: Clinical and Epidemiologic Centers
The purpose of this project is to establish a national network that will have responsibility for the development, evaluation, and validation of biomarkers for earlier cancer detection and risk assessment.

RFA CA-99-013
Cancer Intervention and Surveillance Modeling Network (CISNET)
The goal of this research is 1) to help answer questions in the analysis of cancer incidence and mortality trends, 2) to determine whether recommended interventions are having their expected population impact, and (3) to predict the potential of new interventions on national trends.

RFA CA-99-014
Basic Biological Research on Cancer-Related Behaviors
The Division of Cancer Control and Population Sciences (DCCPS) of the National Cancer Institute (NCI) invited research grant applications on the biobehavioral basis of behaviors which increase the risk of cancer, cancer-related morbidity, or progression of cancer.

PAR-99-006
Small Grants Program for Behavioral Research in Cancer Control
The Small Grants Program is designed to aid and facilitate the growth of a nationwide cohort of scientists with a high level of research expertise in behavioral cancer control research. Small grants are short-term awards, using the R03 mechanism to provide support for pilot projects, development and testing of new methodologies, secondary data analyses, or innovative projects that provide a basis for more extended research. Studies in the broad range of program areas focused on behavior and cancer are appropriate for this program.

PAR-99-167
Specialized Program of Research Excellence in Human Cancer
The Organ Systems Branch of the Office of the Deputy Director for Extramural Science at the National Cancer Institute (NCI) invites grant applications (P50) for Specialized Programs of Research Excellence (SPORE) in organ-specific cancers. Applicant institutions must be able to conduct the highest-quality, balanced translational research on the prevention, etiology, screening, diagnosis, and treatment of a specific organ site cancer.

PA-99-014 (NCI, AHCPR, NIDCR)
Economic Studies in Cancer Prevention, Screening and Care
The goal of this program announcement is to generate new economic knowledge that will promote the optimal design of cancer prevention and control trial studies and interventions and will facilitate the formulation of effective health care policy related to cancer prevention and control.

PA-99-082
Development of Digital Mammography Displays and Workstations (SBIR/STTR)
The purpose of this Program Announcement is to alert the investigator community of the need for and NCI interest in a concerted effort to overcome the problems of display for digital mammograms.

PA-99-162 (NCI, NICHD, NIDDK, NIA, NIEHS)
Stages of Breast Development: Normal to Metastatic Disease
The purpose of this program announcement is to support studies on the molecular, cellular, endocrine, and other physiological influences on the development and maturation of the normal mammary gland and alterations involved in early malignant and metastatic breast cancer.

RFA CA-00-002
Molecular Target Drug Discovery for Cancer
The Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, and the Chemoprevention Agent Development Research Group, Division of Cancer Prevention invited cooperative agreement applications to exploit molecular targets for drug discovery. New insights into our understanding of cancer cell biology provide a new opportunity for a fundamental reordering of approaches to cancer drug discovery.

RFA CA-01-002 (NCI, ORMH)
Comprehensive Minority Institution/Cancer Center Partnership
The purpose of this project is to increase the cancer research capabilities at the Minority-Serving Institutions; to increase the number of minority scientists engaged in cancer research and other related cancer activities; and to improve the effectiveness of NCI-designated Cancer Centers in developing and sustaining activities focused on the disproportionate incidence, mortality, and morbidity in minority populations in the region the cancer center serves.

RFA CA-01-013
Cancer Care Outcomes Research and Surveillance Consortium
This Request for Applications is the first major step by the NCI to support the development of a system for obtaining details about cancer care beyond the initial diagnosis and limited treatment data that are now routinely collected in high-quality, population-based cancer registries. This research will help build the information base needed for measuring and improving the quality of cancer care in the United States.

RFA HD-00-007 (NICHD, NIAID, NCI, NIDCR, NIMH, NCCAM, Fogarty International Center)
Global Network for Women's and Children's Health Research
The purpose of this solicitation is to establish an innovative and flexible research network that will be responsive to the most critical existing and emerging health needs and public health problems of women and children throughout the world.

RFA AT-00-001 (NCCAM, NCI, NHLBI)
Centers for Complementary and Alternative Medicine Research
This report urges a systematic analysis of alternative treatments and their effects on major disease, health, and wellness.

PA-00-001 (NIA, NCI, NINR)
Aging Women and Breast Cancer
The purpose of this broad-based program announcement is to expand the knowledge base on breast cancer in older women through studies in biology, clinical medicine, epidemiology, and the behavioral and social sciences.

PA-00-127 (NINR, NCI, NCCAM, NIAID, NIDCR, NIMH, NIA)
Quality of Life for Individuals at the End of Life
In a broad sense, the purpose of this program announcement is to support studies on enhancing the quality of life remaining for individuals who are nearing the end of their lives.

PA-00-086 (NCI, NIDCR)
Molecular Epidemiology of HIV-Associated Cancers
The purpose of this project is to better understand the molecular epidemiology and role of cofactors in the etiology of pre-neoplastic conditions and cancers occurring among persons infected with HIV, specifically those cancers associated with the DNA viruses, including human papilloma virus, Epstein-Barr virus, and human herpes virus 8/Kaposi sarcoma-associated herpes virus.

SELECTED MEETINGS OF INTEREST

(Sponsored or co-sponsored by the NCI)

Cancer Survivorship: Research Challenges and Opportunities for the New Millennium (1999 Annual Workshop on Cancer Survivorship Research; 3/8-9/99)

Third National AIDS Malignancy Conference (NIH Bldg. 45, 5/26-27/99)

NCI Youth Tobacco Investigators Meeting (Bethesda, MD, 6/17-18/99)

DES Research Update 1999: Current Knowledge, Future Directions (NIH Bldg. 45, 7/19-20/99)

State of the Science Lung Cancer Conference-Molecular Targets for Therapy in Lung Cancer (Bethesda, MD, 9/14-15/99)

Long Island Breast Cancer Study Project-Town Meeting (New York, NY, 10/18-21/99)

Colorectal Cancer Progress Review Group Roundtable Meeting (San Francisco, CA, 1/5-8/99)

Workshop on Circadian Disruption as Endocrine Disruption in Breast Cancer (Bethesda, MD, 3/20-21/00)

Translational Research in Gynecologic Cancers (Chantilly, VA, 5/4-6/00)

State of the Science Meeting - Lung Cancer (Bethesda, MD, 6/14-15/00)

Brain Tumor Progress Review Group Roundtable Meeting (Leesburg, VA, 7/5-8/00)

Breast Cancer Think Tank (BCTT) 2000 Retreat (Chantilly, VA, 7/27-28/00)

Healing Works: The First National Conference on Lesbians and Cancer (Washington, DC, 9/21-23/00)

Adjuvant Therapy for Breast Cancer-NIH Consensus Development Conference (NIH Bldg. 45, 11/1-3/00)

Key Words

Introduction: Center to Reduce Cancer Health Disparities
Cross-Cutting Initiatives: angiogenesis, cancer screening, chemoprevention, end-of-life care, health disparities, nutrition, signaling pathways.
Breast Cancer: adjuvant therapy, BRCA1, BRCA2, Breast Cancer Prevention Trial (BCPT), Buserelin, caretaker genes, chemoprevention, Consensus Conference, diet, digital mammography, ductal carcinoma in situ (DCIS), environmental factors, estrogen receptors, genetic factors, Herceptin(r), hormones, hormone replacement therapy (HRT), ionizing radiation, isoflavonoids, lifestyle factors, lumpectomy, mammogram, mastectomy, Multiple Outcomes of Raloxifene Evaluation (MORE), Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, prevention, prophylactic mastectomy, prophylactic oophorectomy, radiation, Raloxifene, Study of Tamoxifen and Raloxifene (STAR), Tamoxifen, tumor suppressor genes.
Cervical Cancer: ALTS trial, ASCUS, cervical hyperplasias, cisplatin, human papilloma virus (HPV), LSIL, pap test, screening tool, sexually transmitted diseases, smoking.
Ovarian Cancer: CGAP, chemotherapy, fertility, oral contraceptives, prophylactic oophorectomy, Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO), SPORE, stem cell transplant, tubal sterilization.
Uterine and Other Gynecologic Cancers: corpus uteri, diethylstilbestrol (DES), endometrial cancer, endometrium, hormone replacement therapy, smoking.
Lung Cancer: dopamine, dopamine receptors, Lung Screening Study, nicotine, PLCO, secondhand smoke, smoking, tobacco, Transdisciplinary Tobacco Use Research Centers (TTURCs).
Colorectal Cancer: adjuvant therapy, Cooperative Family Registry for Colorectal Cancer Studies, diet, exercise, etiology, heterocyclic amines (HCA), NSAIDs, PLCO, polycyclic aromatic hydrocarbons (PAH).
AIDS: AIDS-Associated Malignancies, cervical cancer, HIV, HIV microbicides, Thalidomide.