Cancer continues to take a devastating toll on American women. In 1999, an estimated 598,000 women will be diagnosed with cancer, and approximately 272,000 women will die of the disease. Despite these grim statistics, our Nation is making progress in the fight against cancer. Between 1990 and 1995, cancer incidence and mortality rates dropped significantly, reversing an almost 20-year trend of increasing cancer cases and deaths in the United States. Unfortunately, these promising statistics did not apply to all racial and ethnic groups. The National Cancer Institute (NCI) is committed, through targeted research, to understanding these disparities and eliminating them.
The NCI conducts a broad-based research program, as well as research specific to cancers in women, in order to advance our knowledge and understanding of all types of cancer. The NCI supports and coordinates a comprehensive research program to reduce the burden of cancer by investigating the continuum of breast cancer research and care, from "bench to bedside." Extensive education and information programs are directed toward the public, patients and their families, and health professionals through resources such as the CancerTrials Website (http://cancertrials.nci.nih.gov/), CancerNet (http://cancernet.nci.nih.gov/), and the Cancer Information Service (CIS) (http://cis.nci.nih.gov/). The CIS promotes community outreach activities and provides information about state-of-the-art detection and treatment, and ongoing clinical trials in prevention, early detection, and treatment through a network of regional offices accessed through a toll-free telephone number (1-800-4-CANCER).
A major research effort of the NCI is directed at understanding the genetic and molecular events that occur as a normal cell evolves to malignancy. The NCI has established the Cancer Genetics Network in order to link centers that test, monitor, and counsel individuals for genetic susceptibility, evaluate genetic and environmental factors that contribute to cancer and speed the application of findings for clinical use. Family registries for colon, breast, and ovarian cancers are now available to provide information to researchers on inherited genetic mutations. The Genetic Annotation Initiative, begun in FY1998, is a large effort to develop a comprehensive catalog of variations in the DNA sequences of each cancer-related gene. Projects and programs such as the Mouse Cancer Genome Anatomy Project and Mouse Models of Human Cancer Consortium, as well as studies in simple organisms like yeast's, provide mechanisms for the development of useful preclinical models to facilitate the study of cancer genes in living systems. By identifying the signatures of cells as they undergo malignant transformation, we will be better able to detect and diagnose individual cancers. The Tumor Gene Index (TGI), a part of the Cancer Genome Anatomy Project (CGAP), has the goal of generating a complete index of all expressed genes in cancer cells. The TGI was implemented in 1997 and has already produced more than 15,000 DNA sequences for breast cancer alone, resulting in the discovery of over 350 human genes never seen before in any human tissue. Scientists are assessing the potential value of these genes in molecular diagnostics and early detection of cancer. CGAP also supports the development and dissemination of new technologies that will allow high throughput analysis of gene and protein expression as well as mutation detection. More information on CGAP can be found on line at http://www.ncbi.nlm.nih.gov/ncicgap/.
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 which includes the NCI Cancer Centers, Cooperative Groups, Specialized Programs of Research Excellence, and Community Clinical Oncology Program. A recent review of the clinical trials program has resulted in steps to create a more efficient and effective clinical research effort. This includes a new program, Rapid Access to Intervention Development that will help to move potential new treatments from "bench to bedside," and the development of a Cancer Informatics Infrastructure to facilitate the flow of information among researchers, clinicians, and the public. A number of important advances in treatments for cancers in women have been achieved through NCI clinical trials in the last two years. These include verification of the benefits of Taxol® for the treatment of breast and ovarian cancer; the testing of Herceptin®, a monoclonal antibody, for the treatment of advanced breast cancer; the finding that preoperative chemotherapy for breast cancer can reduce the need for mastectomy; and new clinical guidelines for the treatment of advanced cervical cancer with combined chemotherapy and radiation. In 1998, the Breast Cancer Prevention Trial demonstrated a 45 percent reduction in breast cancer incidence among high-risk participants who took the drug tamoxifen. Further studies will continue to investigate the use of tamoxifen and other related Selective Estrogen Response Modifiers as chemopreventives for breast cancer. Clinical research studies have also helped to develop methods for the management of symptoms associated with disease and the side-effects of chemotherapy. More information about NCI cancer trials is available at http://cancertrials.nci.nih.gov/.
Approximately eight million living Americans have been diagnosed with cancer sometime in their lifetime. Cancer survivors may currently be in treatment, in remission from their disease, or considered to be cancer-free for a number of years. These individuals deal with unique medical, legal, social, and emotional consequences of their disease. The NCI supports a broad, cross-disciplinary portfolio of research related to quality of life. Ongoing research studies investigate improved treatments for cancer pain, interventions to alleviate the side effects of therapy, less invasive types of cancer surgery, and the effectiveness of support groups to help patients and their families deal with the emotional and psychological effects of the disease. Measurement of a patient's quality of life is now a routine component of many NCI-supported clinical trials. Other studies are focused on patient rehabilitation to deal with disease- and therapy-related after effects. For the more than 1,500 Americans who die each day from cancer, NCI is collaborating with other NIH institutes in sponsoring studies to improve the delivery of palliative care. As methods of early detection and treatment improve, many more people are surviving cancer longer, including many children diagnosed with cancer prior to age 21, who will develop to adulthood. Studies of long-term survivors are exploring potential problems such as cardiac function, reproduction, and second cancers. An issue that many people with cancer must deal with is the cost of treatment and rehabilitation. NCI is dedicated to ensuring quality care, including rehabilitation after treatment for all cancer patients. Agreements with the Department of Defense and the Veterans Administration will help insured individuals to receive full coverage on all NCI-sponsored prevention, detection, diagnosis, and treatment clinical trials, improving access to state-of-the-art care for thousands of subscribers.
(Keywords: cancer patient advocacy, cancer survivorship, cancer trials resources, CGAP, Cancer Genome Anatomy Project, complementary and alternative medicine, Director's Consumer Liaison Group, DCLG, Office of Cancer Survivorship, Office of Liaison Activities, pain control)
Cancer continues to take a devastating toll on American women. In 1999, an estimated 598,000 women will be diagnosed with cancer, and approximately 272,000 women will die of cancer. Despite these grim statistics, our Nation is making progress in the fight against cancer. Between 1990 and 1995, our cancer incidence and mortality rates dropped significantly, reversing an almost 20-year trend of increasing cancer cases and deaths in the United States. This encouraging trend continued in 1996; indeed, the incidence rate for all cancers combined declined an average of nearly 1 percent per year between 1990 and 1995. These welcome trends were seen for most age groups, for both men and women, and for most racial and ethnic groups. The exceptions were black males, in whom the rates continued to increase, and Asian and Pacific Islander females, in whom the rates were level. These exciting statistics do not capture the improved quality of life experienced by many of the millions of cancer survivors in this country.
The National Cancer Institute (NCI) is committed to continuing efforts to reduce the toll of cancer through targeted research. The NCI supports and coordinates a comprehensive research program that investigates all aspects of cancer, including biology, risk, prevention, treatment, and control. 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. Through its strategic planning process, the NCI has identified many of the questions that need to be answered and areas of research and care that need to be further addressed in order to advance our knowledge in the study of cancer. In order to strengthen the nation's cancer research infrastructure the NCI has implemented a number of initiatives. The Nation's Investment in Cancer Research: A Budget Proposal for Fiscal Year 2000 (http://plan2000.cancer.gov/) includes descriptions of these initiatives. The initiatives are not, for the most part, disease-specific, but address problems and opportunities common to all tumors and emphasize the development of technologies and approaches applicable to many cancers.
About This Report. This report describes many of the accomplishments of NCI's cancer research programs during fiscal years 1997 and 1998 addressing cancers specific to or primarily affecting women or those with high incidence or mortality among women.
Cancer Genetics. Understanding of the molecular and genetic signatures of normal and malignant cells and the events that characterize malignant progression will provide answers to key questions critical to progress in all areas of cancer research. The NCI has established the Cancer Genetics Network in order to link centers that test, monitor, and counsel individuals for genetic susceptibility, evaluate genetic and environmental factors that contribute to cancer and speed the application of findings for clinical use. Family registries for colon, breast, and ovarian cancers are now available to provide information to researchers on inherited genetic mutations. The Genetic Annotation Initiative, begun in FY1998, is a large effort to develop a comprehensive catalog of variations in the DNA sequences of each cancer-related gene. Projects and programs such as the Mouse Cancer Genome Anatomy Project and Mouse Models of Human Cancer Consortium, as well as the support of studies in simple organisms like yeast's, provide mechanisms for the development of useful preclinical models to facilitate the study of cancer genes in living systems. By identifying the signatures of cells as they undergo malignant transformation, we will be better able to detect and diagnose individual cancers. The Tumor Gene Index (TGI), a part of the Cancer Genome Anatomy Project (CGAP), has the goal of generating a complete index of all expressed genes in cancer cells. The TGI was implemented in 1997 and has already produced more than 15,000 DNA sequences for breast cancer alone, resulting in the discovery of over 350 human genes never seen before in any human tissue. Scientists are assessing the potential value of these genes in molecular diagnostics and early detection of cancer. CGAP also supports the development and dissemination of new technologies that will allow high throughput analysis of gene and protein expression as well as mutation detection. More information on CGAP can be found on line at http://wwwncbi.nlm.nih.gov/ncicgap/.
Through surveillance activity, the NCI monitors trends in cancer incidence, survival, risk factors, and death among populations. Our primary means of measuring these trends is through the Surveillance, Epidemiology, and End Results (SEER) database (http://www-seer.ims.nci.nih.gov). Availability of surveillance data collected by the 11 population-based cancer registries throughout the United States enables researchers to study the impact of cancer on the general population. Trends in cancer incidence and mortality; and patterns and outcomes of prevention, diagnosis, treatment, and control methods can be studied in order to identify geographic disparities, high risk groups, and effective interventions. The ability to collect health-related information on populations is critical to evaluating the effectiveness of prevention and control interventions. In addition to SEER, the NCI supports a diverse portfolio of surveillance research efforts that includes the Breast Cancer Surveillance Consortium which is being enhanced to collect more complete data on risk factors for breast cancer incidence, prognosis, and quality of life. Other initiatives focus on population-based studies for various cancers, survival information for different racial and ethnic groups, the development of networks of investigators in managed care organizations to strengthen the surveillance research capacity, and studies of cancer outcomes in clinical trials. The NCI has established a Surveillance Implementation Group to help develop plans and research priorities to guide future surveillance efforts and ensure that we are keeping pace with the needs of the cancer research community.
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 which includes the NCI Cancer Centers, Cooperative Groups, Specialized Programs of Research Excellence, and Community Clinical Oncology Program. A recent review of the clinical trials program has resulted in steps to create a more efficient and effective clinical research effort. The NCI is focusing efforts on areas of research which have previously been less emphasized and are important to improvement of the quality of life of all cancer patients. Some of these efforts are described below.
Pain Control. Pain, one of the most important quality of life issues facing cancer patients, can be one of the most debilitating side effects of the disease. Unfortunately, pain is widely under-treated among people with cancer, especially the elderly. Recognizing the need for improved treatment of cancer pain, the NCI sponsors several ongoing pain control-related clinical trials and has produced a number of pain-related publications for both patients and health professionals. In addition, the Johns Hopkins University Oncology Center, through an NCI grant, has produced a patient/health professional resource, Controlling Cancer Pain. This resource includes a video and brochure, available in both English and Spanish, and a pain rating instrument. Johns Hopkins and the NCI are now exploring a partnership for production of Web-based educational software to accompany the materials and distribution of the resource package. Finally, the Agency for Health Care Policy and Research has recently updated its guidelines for pain management for clinicians. A quick reference version for clinicians of these guidelines can be found here.
Cancer Survivorship. It is estimated that 8.2 million Americans alive today have a history of cancer; some of these individuals might be considered cancer free, while others continue to battle their disease. As early detection and treatment methods improve and more people with cancer survive their disease, the resulting increase in the number of cancer survivors has presented us with a new challenge: how best to serve the needs of cancer survivors, who face unique medical, social, legal, and psychological issues. In response to this challenge, the NCI has established the Office of Cancer Survivorship, which supports research covering the spectrum of issues facing cancer survivors. Research areas supported by the Office include the long-term medical and psychosocial effects of treatment, factors that predispose survivors to second malignancies, reproductive problems following treatment, and insurance and employment issues.
Complementary and Alternative Medicine. More cancer patients than ever before are turning to complementary and alternative medicine (CAM) to treat disease. Complementary and alternative medicine covers a broad range of healing philosophies, approaches, and therapies, which can be used in a variety of ways. Therapies are used alone (often referred to as alternative), in combination with other alternative therapies, or in addition to conventional therapies (referred to as complementary). Some approaches are consistent with physiological principles of Western medicine, while others draw on healing systems with a different origin.
The NCI, in 1998, created the Office of Cancer Complementary and Alternative Medicine, for liaison activities between the NCI, researchers, and the CAM communities in order to encourage collaboration and joint research initiatives. The NCI collaborates with the National Center for Complementary and Alternative Medicine on key projects, and is moving ahead with a number of projects to evaluate different types of CAM therapy, including shark cartilage for the treatment of cancer and green tea for cancer prevention. Communication and education efforts related to CAM are also ongoing.
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; and from the Cancer Information Service's (CIS) toll free number, 1-800-4-CANCER. In response to a report from the Office of the Inspector General, the CIS has upgraded it telephone and computer technology and developed a more efficient system of collecting community services referral information by partnering with other organization. Taking advantage of the capabilities of the World Wide Web, the NCI makes information available through its website resources, including the CancerNet™ (http://cancernet.nci.nih.gov), which provides information summaries on various cancer sites; and the CancerTrials website (http://cancertrials.nci.nih.gov), which provides information about ongoing prevention, detection, diagnosis, and treatment clinical trials, links to databases of ongoing studies, and general information about clinical trials. The Physician Data Query (PDQ) database provides current information on cancer prevention, screening, treatment, and supportive care, as well as active research studies and directories of physicians, genetic counselors, and organizations involved in cancer care. Information, updated monthly, is available in technical and non-technical language, in English and Spanish, on the CancerNet™ website. PDQ has been undergoing a comprehensive overhaul to improve the scope and level of the content and to address user interface issues such as interactivity, navigability, and access. New components of the Cancer Informatics Infrastructure include mechanisms to improve the efficiency of the drug development process, an electronic reporting system for rapid reporting of standardized data for adverse experiences with NCI investigational agents, a revised set of Common Toxicity Criteria, and mechanisms to facilitate efficient communication between physicians involved in clinical trials.
Cancer Patient Advocacy. The NCI Office of Liaison Activities (OLA), created in 1996, has two goals: 1) to create and maintain ongoing, two-way communication and information exchange between the national cancer advocacy organizations and NCI; and 2) to cooperate and collaborate with these groups in areas of mutual interest. In 1997, NCI established its first all-consumer advocate advisory committee, the National Cancer Institute Director's Consumer Liaison Group (DCLG), coordinated by OLA. The DCLG includes 15 consumer advocates who assist NCI staff in identifying appropriate consumer advocates to serve on key advisory bodies and participate in discussion of the broad development of NCI programmatic and research priorities. DCLG members also serve as a conduit for communication and facilitate the maintenance of a strong partnership between the NCI and the consumer advocate community.
(Keywords: angiogenesis, BRCA1, BRCA2, Breast Cancer Risk Assessment Tool, chemotherapy prior to surgery, diet, Early Detection Research Network, genetic factors, HER2/neu Herceptin®, hormone replacement, imaging technologies, mammography, markers of disease, oral contraceptives, outcomes, prevention, prophylactic mastectomy, racial differences, Raloxifene, risk factors, screening recommendations, tamoxifen, Taxol, tissue resources, vascular endothelial growth, VEGF)
After increasing rapidly from 1973-90, the rate of breast cancer incidence in American women has leveled off. Mortality rates have dropped or leveled off for almost all women. For White and Hispanic women, mortality rates dropped between 1990 and 1995. The rate of increase in mortality in African American women has slowed from 16% between 1980 and 1989 to 1% between 1989 and 1993. These figures indicate that increased efforts at outreach, education, and control are needed, especially for older African American women.
In spite of research advances, from early detection through treatment, breast cancer remains the second leading cause of cancer death for women, second only to lung cancer. In 1999, it is expected that 175,000 women will be diagnosed with the disease and 43,300 will succumb. Approximately 2 million women have been diagnosed with breast cancer at some point in their lives. Additionally, it is expected that 1,300 men will be diagnosed and 400 will die from breast cancer in 1999. Over the past two decades, much progress has been made in understanding how breast cancer develops and progresses, why some tumors are more aggressive than others, and why some women are more likely to die of the disease.
New therapies are being developed which help to improve quality of life and extend disease-free survival. Although these advances have been significant, there are many questions yet to be answered in order to alleviate the burden of breast cancer and ultimately prevent it. In order to optimize the use of our research resources and pursue research opportunities which will lead to answers to critical scientific questions, the NCI, in 1997, established the Breast Cancer Progress Review Group (PRG). The overall goal of the PRG was to provide recommendations for a national breast cancer research agenda, consisting of a description of ongoing scientific activities and investigations and an enumeration of additional, unaddressed scientific opportunities that should be undertaken in priority order in light of the current activities.
The PRG presented their report to the NCI in August 1998. The complete report, Charting the Course: Priorities for Breast Cancer Research, is available online at http://prg.nci.nih.gov/breast/finalreport.html.
Biology
Angiogenesis. Angiogenesis, or new blood vessel formation, is essential for the support of solid tumor growth. Studies in mice have shown that a protein, vascular endothelial growth factor (VEGF), is over expressed in human breast carcinomas, as well as in in situ carcinomas. These studies indicate that angiogenesis starts before the breast carcinomas become invasive. It was also found that when VEGF was suppressed, the breast tumors did not grow. Research has shown that there are a number of angiogenesis factors which appear to be responsible for vascularization at different stages of tumor development.
Many studies to understand different angiogenesis factors, as well as factors which are known to inhibit the action of angiogenic factors are ongoing. Understanding of these processes may provide targets for therapy. The first generation of anti-angiogenic drugs is being tested in clinical trials. Because angiogenesis only occurs in processes like wound healing and tumor growth, the drugs do not affect healthy tissue and have few side effects, therefore offering the potential for exciting new therapies.
Markers of Disease. Several markers of disease, most notably, estrogen receptor and HER2/neu, have been identified, and have provided important targets for therapy. Other potential cellular and genetic markers of disease are being studied as potential targets for therapy and also to help in understanding apparent differences in aggressiveness of cancer in population subgroups, especially in African American women. The NCI funds resources which make breast cancer tissue specimens available to researchers to study potential markers of disease.
Risk Factors
BRCA1/BRCA2. The identification of two important genes associated with inherited breast cancers, BRCA1 and BRCA2, has important implications for understanding the molecular genetic basis of the disease and ultimately, the prevention and treatment of women who have alterations in these genes. Research is under way to understand the normal function of these genes and how their mutation leads to the development of cancer. It is known that BRCA1 and BRCA2 are tumor suppressor genes, which function to prevent some stage of tumor development. Mutations in these genes only appear in a few inherited tumors, and are rarely in sporadic cancers or in normal tissue, indicating that their function is very specific. Recent research findings have indicated that BRCA2 and a protein called Rad51 are part of a complex of proteins that repairs damaged DNA. If their activities are impaired or lost in breast epithelial cells, the result may be an unstable genome and subsequent tumorigenesis. This finding may have important implications for a new target for therapy.
Alterations in the genes, BRCA1 and BRCA2 are associated with a substantially increased risk of breast, ovarian, and prostate cancers. A community-based study of over 5,000 volunteers from the Washington, D.C. Ashkenazi Jewish community was initiated to determine the cancer risk associated with mutations in BRCA1, as well as BRCA2. Approximately 2% of the volunteers were identified as having one of three mutations reported to be common in Ashkenazi Jews. The average risk for this group for breast cancer was found to be 56% by age 70 compared with a 13% chance for women without the mutations; and a risk of 16% for ovarian cancer by age 70 compared with a nearly 2% chance for non-carriers. These risks, although significantly elevated, were lower than earlier estimates based on high risk families. The study also showed the risk for prostate cancer was increased to 16% by age 70 compared with a nearly 4% risk for non-carriers. Importantly, it was also shown that some individuals who had one of the three mutations did not have a personal or family history of breast or ovarian cancer, suggesting that factors other than having a BRCA1 or BRCA2 mutation affect risk, such as other genes or environmental agents.
Responding to an important need in the research community, NCI established the Cooperative Family Registry for Breast Cancer Studies (CFBCRS) in 1995. The resource, which now includes data from more than 5,000 families, provides researchers with biological and data resources needed to explore key questions about inherited mutations in cancer susceptibility genes. Informatics support services established by the NCI allow the resources of the registry to be shared with researchers for use in population-based genetic studies. The registry also provides follow-up epidemiological data, data on recurrence, and new morbidity and mortality in the participating families. Additional information on the CFRBCS can be found on line at: http://www-dccps.ims.nci.nih.gov/CFRBCS.
Other Risk Factors. Researchers are investigating a number of other factors and their possible roles in the etiology of breast cancer in all women. These factors include diet, body size, endogenous hormones, and lifestyle (including alcohol consumption, smoking, and physical activity), as well as potential gene-environment interactions including environmental exposures to pesticides and other contaminants.
Diet. A large case-controlled study of breast cancer in Asian-American women found that the increased intake of soy products rich in phytoestrogens may protect against breast cancer. Preliminary studies of the relationship between breast cancer and the genetic variation in the superoxide dismutase gene have shown that women who ate foods rich in antioxidants had decreased disease risk. The gene, which plays a role in the maintenance of reactive oxygen species in mitochondria, is known to be predictive of breast cancer risk. Breast cancer incidence rates in the United States have historically been four to seven times higher than in China or Japan. When these women migrate to the United States, their breast cancer risk rises over several generations and reaches that for White women in the U.S. The results of the population-based study suggest that weight maintenance and/or weight reduction as an adult, possibly accompanied by specific changes in diet and physical activity, may have a significant and rapid impact on breast cancer risk. Other studies have shown that alcohol intake and tobacco use are directly associated with increased disease risk.
Oral Contraceptives and Hormone Replacement. Several studies have examined the effects of oral contraceptives and menopausal hormones and their possible association with breast cancer risk. A slightly elevated level of risk for breast cancer was associated with oral contraceptive use in very thin women and those with high levels of alcohol consumption. Studies of menopausal women who had used oral contraceptives for 10 or more years and hormone replacement for 3 or more years had a somewhat elevated risk of breast cancer compared with those women who had not used either oral contraceptives or hormone replacement. This preliminary information requires further confirmatory studies.
Racial Differences. Although the mortality rate from breast cancer for African American women under age 50 has declined, it continues to be higher than that for White and Hispanic women. A large case-control study of breast cancer among younger women assessed reasons for the varying incidence rates among White and African American women. Examination of a variety of risk factors failed to explain racial differences at young ages. In older women, the higher rates in White women appeared to be associated with fewer births, later ages at first birth, and slightly higher risks associated with reproductive and menstrual factors. Other population-based, case-control studies are examining differences in breast cancer among White and African American women in varying geographic areas of central and eastern North Carolina. The study integrates epidemiology and molecular biology to explore risk factors for breast cancer, including possible gene-environment interactions. Additional studies, nearly complete, are focusing on environmental risk factors, such as organochlorine exposure in Alaska Native women and exposure to DDT and other organochlorines in rural, low-income, predominantly African American women.
Breast Cancer Risk Assessment Tool. The Breast Cancer Risk Assessment Tool, developed in 1998 by scientists at the NCI and the National Surgical Adjuvant Breast and Bowel Project, is a computer program that women and their health care providers can use to estimate a woman's chances of developing breast cancer based on several recognized risk factors. The Breast Cancer Risk Assessment Tool also provides information on the drug tamoxifen. The Risk Tool may be obtained by accessing the CancerTrials website, http://cancertrials.nci.nih.gov, or by calling the Cancer Information Service at 1-800-4-CANCER.
Screening and Early Detection
Imaging Technologies. The NCI supports a number of research initiatives to improve conventional mammography and develop alternative imaging technologies to detect and characterize breast tumors. Currently, high-quality mammography is the most effective method for early detection of breast abnormalities. The NCI funds research to further reduce the radiation dosage; enhance image quality; develop and evaluate digital mammography as an improvement over the conventional, film-based technique; develop statistical techniques for computer-assisted interpretation of digitized images; and enable long-distance image transmission technology (teleradiology) for clinical consultations. NCI also supports research on non-x-ray based technologies such as magnetic resonance imaging (MRI) and breast-specific positron emission tomography (PET) to detect disease.
Screening Recommendations. In 1997, the NCI's National Cancer Advisory Board concluded that breast cancer screening for women between the ages of 40 and 49 is beneficial. The NCI developed a risk-based system to assist women in their forties and their physicians in making decisions about when to initiate regular mammographic screening. The methods allow a woman in this age group to compare her risk of breast cancer to that of a woman aged 50 without risk factors, and for whom mammographic screening would usually be recommended on a regular basis. Screening is recommended if a woman in her forties has any of six strong risk factors for breast cancer. Women without any of the six strong risk factors can assess their need for mammographic screening by multiplying relative risks corresponding to three weaker breast cancer risk factors. Separate relative risk tables are used for African American and White women, since breast cancer incidence rate rises more rapidly among black women in their forties than among white women.
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. To optimally evaluate the performance of mammography in a community setting, the sensitivity, specificity and predictive value of mammography in community screening programs should be determined by linkage with cancer outcomes. In response to the need for such an evaluation program, the NCI established the Breast Cancer Surveillance Consortium in 1994. Nine sites throughout the United States are participating. The members of the Consortium have defined a standardized set of data variables including patient demographic and health history, radiologic, diagnostic follow up, and pathologic outcomes. By the year 2000, the database will contain information from nearly 3.2 million screening mammographic examinations and over 24,000 breast cancer cases. A collaborative effort has been undertaken by the International Breast Cancer Screening Network, an effort administered by the NCI, to produce international data on the policies, funding and administration, and results of population-based breast cancer screening.
A successful community-based strategy to increase mammography use among low-income women living in public housing was planned and conducted in collaboration with the American Cancer Society. The intervention, called Friend to Friend, consisted of a health professional talk, small group discussions, and an opportunity to request a free mammogram or a mammogram reminder if screening was up-to-date. 27 percent of age-eligible women (low-income, medically indigent, minority women aged 40 and older residing in 41 public housing high-rise buildings) participated in the program. A post-intervention survey showed that mammography use was significantly higher among women who participated in the intervention, suggesting that a multidimensional community-based intervention reaching women within their social environment can significantly increase mammography utilization. This research is unique among community-based mammography interventions in that it has been successfully adopted by the community.
In October 1998, the NCI and the Health Care Financing Administration announced a joint effort to increase the awareness of the importance of regularly-scheduled screening mammograms among women aged 65 and older and health care providers. The national health promotion effort also encourages women to continue to get regularly-scheduled screening mammograms and seeks to increase awareness and use of the expanded Medicare screening mammogram benefit. Few Medicare beneficiaries are aware of the new expanded benefit for annual screening mammograms, and even fewer utilize the benefit. A national media campaign was launched during National Breast Cancer Awareness Month, October 1998. The breast cancer and mammography education program developed a series of publications in English and Spanish, Mammograms: Not Once But for a Lifetime. The information, as well as other educational materials on cancer are made available to the public through the NCI website, http://www.nci.nih.gov and through the NCI Cancer Information Service, 1-800-4-CANCER (1-800-422-6237).
Early Detection Research Network. In 1999, the NCI plans to establish a multi-institutional consortium to develop sensitive and specific tests for the molecular early detection of cancer. Breast cancer will be one focus of activity within the Network.
Prevention
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. In 1998, the Breast Cancer Prevention Trial (BCPT) was closed based on the recommendation of the Data and Safety Monitoring Committee because the drug, tamoxifen, was shown to be successful in lowering the risk of developing breast cancer in women at high risk for the disease. Tamoxifen, a Selective Estrogen Response Modulator (SERM), has been used for the last 20 years to treat estrogen receptor positive breast cancer. Over 13,000 healthy women aged 35 to 60+ at high risk for breast cancer participated in the BCPT took either tamoxifen or a placebo for up to 5 years. Data from the trial, implemented by the National Surgical Adjuvant Breast and Bowel Project (NSABP), showed an approximately 49 percent reduction in breast cancer incidence among those participants who took tamoxifen. Women taking tamoxifen also had fewer bone fractures. However, it was also shown that tamoxifen increased the chance of developing three life-threatening health problems: endometrial cancer, pulmonary embolism, and deep vein thrombosis. In September 1998, the Food and Drug Administration's (FDA) Oncologic Drug Advisory Committee recommended expanding the label for tamoxifen to include use for the reduction in the risk of developing breast cancer in high-risk populations. These participants will continue to be followed by the NSABP. Use of tamoxifen is recommended only after careful consideration by a woman and her physician. The NCI has developed a computer risk assessment tool, described above, to aid in making this decision. More information is available on line at http://cancertrials.nci.nih.gov or by calling the Cancer Information Service at 1-800-4-CANCER.
The NCI and the NSABP are continuing to study tamoxifen and other agents that can potentially prevent breast cancer. Raloxifene, a SERM related to tamoxifen that has been approved for the prevention of osteoporosis, is associated with reduced breast cancer incidence in clinical trials. A new large-scale clinical trial, Study of Tamoxifen and Raloxifene (STAR), was approved in late 1998 to compare the effects of tamoxifen to raloxifene in 22,000 women at high risk for breast cancer and will begin accruing participants in early 1999.
Prophylactic mastectomy is one of the options for breast cancer prevention in women at high risk for the disease. Results from a retrospective study of women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993, was published in January 1999. The study was the first to evaluate the efficacy of this measure in reducing the incidence of breast cancer in women considered to be at high risk for the disease. Follow up information for 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy was compared with the number of breast cancers in 403 of their sisters who did not undergo the surgery. Current models would have predicted 20 deaths from breast cancer among the 639 women. During the follow up period, there were 2 deaths. There was a reduction in incidence of 90 percent, supporting a conclusion that prophylactic mastectomy can be effective as a means of reducing breast cancer incidence and mortality in high risk women. This is an option, because of the disfiguring physical and psychological effects, that should be carefully considered by a woman and her physician.
Treatment
Herceptin®. The FDA, in September 1998, approved Herceptin®, a monoclonal antibody, for the treatment of breast cancer. The drug, shown to reduce tumor size when used with standard chemotherapy to treat clinically advanced breast cancer, is an antibody to the protein HER2 or HER2/neu, which is highly expressed in 25 - 30% of breast tumors. Because Herceptin® specifically targets tumor cells expressing the HER2 protein, it does not damage healthy cells and causes few side effects.
Taxol. Findings of a large, NCI multi-center clinical trial have shown that the drug Taxol when used in combination with other standard chemotherapy agents, has a small but significant benefit for breast cancer patients whose disease has spread to nearby lymph nodes. The study, carried out by the Cancer and Leukemia Group B, is considered important because it is the first to show that Taxol may be beneficial in the initial post-surgical treatment of some women with localized, node-positive breast cancer. Prior to this study, Taxol had been used primarily for the treatment of women with more advanced disease. Another NSABP trial for node-positive breast cancer, using Taxotere (docetaxel), a drug similar to Taxol, is still open to new patients. New research demonstrates that higher doses of Taxol are not necessarily more effective in patients with advanced breast cancers, and that patients can be spared the increased toxicities associated with high doses. This study of 475 women with metastatic breast cancer found that higher-than-standard doses of Taxol does not improve survival, and that the drug's efficacy actually declined at higher doses. This finding is particularly relevant given the trend in recent years to increase the dose of chemotherapy agents with the presumption that they will be more active, a hypothesis that has not yet been fully tested.
Chemotherapy Prior to Surgery for Breast Cancer. A study by the NSABP found that women with palpable breast cancers who had preoperative chemotherapy to significantly shrink their tumors, were nearly three times more likely than women who had not had chemotherapy to be able to avoid mastectomy and undergo less disfiguring lumpectomy. This was the first large, randomized study of neoadjuvant chemotherapy in early stage breast cancer versus conventional post-operative adjuvant therapy. Previous trials in the U.S. and abroad have shown that conservative therapy, defined as removal of the tumor itself and adjacent underarm lymph nodes, followed by radiation of the entire breast, results in survival equivalent to modified radical mastectomy.
Racial Differences in Outcomes of Treatment. The NCI supported a study to determine whether African Americans and Whites had comparable treatment responses and outcomes, accounting for estrogen receptor (ER) status and differences in patient characteristics at diagnosis. Survival and related endpoints were examined among African American and White women who participated in two randomized clinical trials: one of women with ER negative tumors and one with ER positive tumors. Results of the study show that African American and White patients with localized breast carcinoma had similar outcomes and benefitted equally from systemic therapy. This suggests that early detection and appropriate therapy among African American patients could contribute to a reduction in the current disparity in breast carcinoma mortality between African American and White women.
(Keywords: ALTS, ASCUS/LSIL Triage Study, cervical cancer awareness program, chemotherapy, chimeric vaccine, detection, follow-up,HPV, human papillomavirus, promoting screening behaviors, risk factors, screening, vaccine development)
Cervical cancer accounts for six percent of all malignancies in women. In 1999, approximately 12,800 American women will be diagnosed with invasive cervical cancer, and an estimated 4800 will die of the disease. Because more than 90 percent of these cases can and should be detected early through the use of the Pap test, the current death rate is far higher than it should be and reflects that, even today, Pap tests are not done on approximately one-third of eligible women.
Cervical cancer is a particular concern for minority and underserved populations in the United States. The incidence and mortality rates for cervical cancer are two to three times higher in Hispanic and African American women than in White women, and cervical cancer is the leading cause of cancer death in certain Hispanic and Asian populations in the United States. According to a report of the President's Cancer Panel, entitled "Concerns of Special Populations in the National Cancer Program," Vietnamese women have the highest cervical cancer incidence in the U.S. and Korean women have the second highest incidence.In Native American women, the disease is much more aggressive and is found in younger women as compared with women of other races. A similar pattern for breast cancer has been observed, but insufficient data exist to support development of a hypothesis. Much of the ethnic differences are attributed to differences in known cervical risk factors, including long intervals since last Pap smear and factors which increase the risk of infection with the human papillomavirus.
Risk Factors. Although many risk factors have been implicated in cervical cancer, studies have shown that 90 percent of cervical cancers are caused by infection with sexually transmitted human papillomaviruses (HPV).
Detection.Cervical cancer screening — most notably through the use of the Pap test — has resulted in dramatic decreases in the cervical cancer death rate which was 45 percent lower for the period 1992 to 1995 than it was just two decades earlier. The Pap test is a relatively simple procedure that should be performed routinely as part of a pelvic exam.
Cervical Cancer Screening and Follow-Up: ASCUS/LSIL Triage Study (ALTS). Each year, two to three million American women learn that their Pap test has uncovered a mildly abnormal change in the cells lining the cervix. These abnormalities are designated ASCUS, for Atypical Squamous Cells of Undetermined Significance, and LSIL, for Low-grade Squamous Intraepithelial Lesions. In most women, ASCUS and LSIL clear up without treatment, but occasionally these abnormalities progress to a precancerous condition or to cervical cancer. To prevent progression to cancer, most women in the United States with a diagnosis of ASCUS or LSIL undergo colposcopy, a procedure in which a physician examines the cervix through a magnifying instrument and then biopsies suspicious areas. Suspicious areas may have to be removed by laser surgery. This approach carries a small risk of complications and is expensive.
To determine the best way to manage these mild cervical abnormalities, the NCI is sponsoring the ongoing ALTS study. Approximately 5,000 women are participating. This study compares three different ways of managing ASCUS and LSIL: immediate colposcopic exam and biopsy (the current standard); a more conservative approach in which women have repeat Pap tests every six months to see whether their lesions regress, stay the same, or begin to convert to a precancerous state; and an "HPV Triage," in which women are assigned treatment based on results of a test for the human papillomavirus (HPV), which is implicated in most cervical cancers. In the latter group, women whose cervical cells contain DNA from certain HPV types associated with cancer have an immediate colposcopy.
Researchers are comparing the three different groups to assess the effectiveness of each management option in detecting the serious abnormalities that can progress to cancer; the acceptability of each option to patients; and the cost effectiveness of each option. Numerous precautions are built into the process to ensure that cancers or precancerous conditions are not overlooked inadvertently.
Promoting Screening Behaviors. Even when effective screening tests are developed, people may not use them. Population scientists study the various kinds of barriers that keep people from using proven cancer screening tests. This knowledge is used to develop effective interventions directed at individuals, health professionals, health care systems, and communities.
In 1996, the NCI Office of Cancer Communications (OCC) launched a cervical cancer awareness program designed to promote the importance of Pap tests in detecting cervical cancer. The focus has been on reaching women ages 65 and older because they have the lowest screening rates. National activities have included the distribution of a media packet that focused on cervical cancer and older women. Additionally, the NCI collaborated with the Healthcare Financing Administration to reprint an NCI cervical cancer publication with Medicare information for older women. Other activities have included conducting research with physicians to identify their attitudes and perceptions of Pap test screening among women 65 and older. Based on this research, a print public service announcement and newsletter article are being developed that encourage physicians to talk to their older patients about Pap test screening. These materials will be promoted through physician publications and newsletters. The OCC produces several cervical cancer and Pap test informational materials for the general public and minority audiences and distributes these through the Cancer Information Service. A publication that discusses treatment options for women who have abnormal Pap tests is under development.
HPV Vaccine Development. Developing a safe and effective HPV vaccine could have an enormous public health impact; such a vaccine has the potential to save thousands of lives and millions of dollars in screening and health care costs each year. The NCI intramural program, in collaboration with industry, is actively working on the development of a vaccine that will prevent HPV infection and, by extension, cervical cancer. Several studies have demonstrated significant progress toward the development of a vaccine. For example, researchers have developed a vaccine using bits of virus-like particles composed of a major structural papillomavirus protein from each of the four HPV-types known to be associated with the majority of cervical cancers. It is hoped that initial studies will show that the vaccine protects against these four HPV types and will prevent more than 80 percent of cervical cancers.
Chimeric Vaccine. In addition to the preventive vaccines under development, NCI is developing a chimeric vaccine — one that might treat existing HPV infection and prevent recurrence. Several treatment vaccines are also being tested, either alone or in combination with other types of treatment, in NCI-sponsored clinical trials.
Concurrent Chemoradiation Therapy. Early in 1999, the NCI mailed a clinical announcement to thousands of physicians stating that strong consideration should be given to adding chemotherapy to radiation therapy in the treatment of invasive cervical cancer. The mailing alerted physicians who treat cancer to the findings of five large clinical studies showing that women had better rates of survival when they received chemotherapy that included the drug cisplatin along with radiation therapy. Prior to this announcement, surgery or radiation alone had been considered standard treatment for this form of cancer. The NCI announcement, along with the press release and Questions & Answers are posted on the CancerTrials Website (http://cancertrials.nci.nih.gov/).
(Keywords: BRCA1, BRCA2, early detection, prevention, treatment)
Ovarian cancer has a higher mortality rate than any other cancer of the female reproductive system. In 1999, approximately 25,200 women in the United States will be diagnosed with ovarian cancer, and approximately 14,500 will die of the disease. Ovarian cancer is highly treatable when detected early, before it has had the chance to spread; however, because the disease is often asymptomatic in its early stages, most patients have widespread disease at the time of diagnosis.
Recognizing the importance of research in ovarian cancer, the NCI, along with the Society of Gynecologic Oncologists and the Public Health Service Office of Women's Health, sponsored a conference in 1997 entitled "New Directions in Ovarian Cancer Research." The participants met to determine the key priorities for ovarian cancer research, and ways to implement those priorities; to outline the challenges and barriers that must be overcome to implement the priorities; and to elucidate the positive effects this research could eventually have on patient care.
In addition, in 1998 the NCI began to solicit applications for the first Specialized Program of Research Excellence (SPORE) in ovarian cancer. SPOREs are programs that focus on translational research (research designed to move laboratory discoveries into patient and population research settings). SPORE institutions conduct high-quality research on the prevention, etiology, screening, diagnosis, and treatment of cancer. In addition, SPOREs are encouraged to conduct rehabilitation and quality-of-life research. NCI-designated Cancer Centers and other institutions are eligible to compete for SPORE awards. It is anticipated that at least one Ovarian Cancer SPORE will be awarded in FY1999.
BRCA1/BRCA2. Approximately 5 to 10 percent of ovarian cancers are familial. Researchers have identified three distinct hereditary patterns: ovarian cancer alone, ovarian and breast cancers, or ovarian and colon cancers. In most families affected with the breast and ovarian cancer syndrome or site- specific ovarian cancer, mutations in the BRCA1 gene have been identified. Some research studies have shown that women with BRCA1 mutations have as much an approximately 16 percent chance of developing ovarian cancer by age 70. Other studies indicate that the risk may be up to 25 percent among women with mutations in the BRCA2 gene.
Interestingly, two retrospective studies of ovarian cancer patients with inherited BRCA1 mutations suggest that these women have improved survival compared to women without mutations. However, the majority of women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, the women in these studies may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.
Early Detection. Because ovarian cancer causes more deaths than other reproductive cancers, it is a part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). The purpose of the PLCO is to determine whether medical tests to detect these common cancers reduce the number of deaths from these diseases. For ovarian cancer, women volunteers between 55 and 74 will have a physical exam of the ovaries, a blood test for the tumor marker known as CA125, and transvaginal ultrasound.
The NCI's Cancer Genome Anatomy Project (CGAP) has begun to develop a comprehensive inventory of all of the genes expressed in tumors. Currently, the CGAP effort has identified nearly 600 unique genes for ovarian tissue. The expression of three of these genes is known and can be linked to ovarian cancer. Research is ongoing to further characterize these and the unknown unique genes and to determine if any of the unique genes are potential biomarkers of disease.
Prevention. There are several ongoing studies dealing with chemoprevention of ovarian cancer. For example, preliminary findings on the effect of nonsteroidal anti-inflammatory drugs (NSAIDs), or over-the-counter analgesics, on risk for ovarian cancer suggest that acetaminophen (paracetamol) may have a protective effect against ovarian cancer. Animal studies demonstrating uterine and ovarian atrophy with administration of high doses of acetaminophen and decreased formation of ovarian cysts at lower doses suggest a biological basis for the observations.
In addition, scientists are researching whether oral contraceptive use, long understood to reduce the risk of ovarian cancer by up to 50 percent among women in the general population, has a similar protective effect among women with BRCA1 or BRCA2 alterations. The latest research has produced important but conflicting findings.
In one study, scientists looked at oral contraceptive use as part of a study on risk for familial ovarian cancer among Jewish women and found that despite the higher incidence of familial ovarian cancer among Jewish women, they were more likely than non-Jewish women to have used oral contraceptives. Overall, women with familial ovarian cancer used oral contraceptives at the same rate as women who did not have ovarian cancer. Further, women who had familial ovarian cancer used oral contraceptives more than women who had non-familial forms of the disease. The findings suggest that oral contraceptives do not protect against familial ovarian cancer as they have been found to do for ovarian cancer in general.
However, scientists in a separate study reported on research on a cohort of 207 women with ovarian cancer who carry mutations in the BRCA1 or BRCA2 genes and 161 of their sisters, some of whom also had these genetic mutations. The study found that patients who had ever used oral contraceptives have an overall 50 percent lower risk of ovarian cancer as compared to their unaffected sisters. If the oral contraceptives were used for more than six years, the risk of ovarian cancer was 60 percent lower than among the sister-controls. The scientists also pointed out that different oral contraceptives contain different combinations of hormones, and their findings do not show that one hormonal mixture is more efficacious than others in preventing ovarian cancer.
Treatment. The PLCO results are not expected for several years. Meanwhile, new treatments have shown significant improvement in ovarian cancer outcomes. For example, within the last two years new standards of optimal therapy for women with advanced ovarian cancer have been established. The monoclonal antibody Herceptin®, currently used to treat women whose breast cancers have not responded to other treatment, is also under study for women with ovarian cancer.
UTERINE AND OTHER GYNECOLOGIC CANCERS
(Keywords: DES, Diethylstilbestrol, endometrial cancer, risk factors, uterine cancer)
Uterine cancer will be diagnosed in about 37,400 women in 1999, making it the eighth most common cancer site in women overall. 6400 deaths will be attributed to this highly treatable cancer. In addition, approximately 2300 cases of vaginal cancer and about 3300 cases of vulvar cancer are expected to be diagnosed in American women.
Risk factors for uterine (endometrial) cancer are thought to include estrogen (including Estrogen Replacement Therapy), early menarche, late menopause, never having children, and use of the breast cancer preventive tamoxifen.
In 1997, enrollment began in a large, NCI-sponsored study of estrogen replacement therapy (ERT) for women who have had cancer of the uterus. The study is designed to resolve the current controversy over the safety of estrogen replacement for survivors of uterine cancer.
Diethylstilbestrol (DES). 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; as many as 3 million women in the United States may have been exposed to DES in utero. In 1971, the first reports emerged linking DES use in pregnancy with the occurrence of clear cell adenocarcinoma (CCA) of the vagina and cervix in exposed daughters, an association that was confirmed through repeated studies.
In a 1998 study, NCI intramural investigators found that, thus far, DES-exposed daughters show no increased cancer risk, except for the previously established risk of CCA. However, they emphasize that the exposed daughters in their study were, on average, only 38 years of age at the time of the study, and that these women will need continued follow-up to determine whether increases in cancer risk occur during the menopausal years. Other aspects of DES under investigation are its effects on fertility and pregnancy among the daughters, cancer risks among sons exposed in utero to the drug, and the effects of DES on mothers who were treated during pregnancy.
A workshop planned for July 1999 will bring together basic and clinical researchers and representatives of the patient advocacy community to discuss the status of research on the long-term effects of DES exposure and to make recommendations for future research.
(Keywords: abnormal DNA methylation, American Stop Smoking Intervention Study, ASSIST, bronchial biopsy, culturally specific smoking cessation environment, detection, diet, nicotine addiction, Photofrin, pneumonia, smoking, sputum biomarker hnRNP A2/B1, Tobacco Research Implementation Trial, TRIG)
It has been estimated that lung cancer affected 80,100 women in 1998, leading to 67,000 deaths. Since 1987, more women have died each year of lung cancer than breast cancer, which, for over 40 years, was the major cause of cancer death in women. Although the current incidence rate of lung cancer among women is remarkably high, the rate of increase has begun to slow in recent years.
Lung cancer incidence remains a major problem in the United States and other countries and although decreasing smoking prevalence promises future decline in rates, many persons remain at high risk. Survival rates for localized lung cancer are dramatically better than for non-localized disease, but most patients are not diagnosed early enough for current therapies to be effective. Attempts to reduce mortality through early detection by conventional modalities have not demonstrated clear-cut benefit. New methods of prevention and early detection are needed to reduce mortality from lung cancer.
Diet. A Missouri study recently found dietary intake of saturated fat to be associated with the overall risk of lung cancer, particularly of adenocarcinoma, among nonsmoking women. In a subsequent study among smokers, the association with saturated fats was not observed. However, an elevated risk of lung cancer was found among women smokers who regularly ate well-done red meat (known to contain polycyclic aromatic hydrocarbons and heterocyclic amines), and a protective effect for those who regularly ate fruits and vegetables.
Pneumonia. A preliminary study has reported a 60 percent increase in lung cancer risk in persons who had evidence of chronic infection with Chlamydia pneumoniae compared to those without evidence of infection. Although these results require confirmation in other studies, the report raises the possibility that in the future, antibiotic treatment may play a role in the prevention of lung cancer.
Environment. In 1993, the U.S. Environmental Protection Agency declared that secondhand smoke, also called environmental tobacco smoke (ETS), is a human carcinogen. Each year about 3,000 nonsmoking adults die of lung cancer as a result of breathing the smoke of others' cigarettes. In an NCI-funded study conducted at the University of Minnesota Cancer Center, scientists recently found a metabolite of a tobacco-specific lung carcinogen in the urine of nonsmoking hospital workers who were occupationally exposed to tobacco smoke. The findings are the first to demonstrate that a metabolite of the tobacco-specific nitrosamine NNK (responsible for inducing lung adenocarcinoma in animal studies) is present in the urine of nonsmokers environmentally exposed to tobacco smoke.
Studies on underground miners exposed to high levels of radon have been used to extrapolate the relative risk of individuals exposed to low levels of radon. Radon exposure in homes is believed to cause an increase in lung cancer risk, especially in cigarette smokers. 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 yield variable results.
During recent years, there has been increased public interest in other substances in the environment or in the work place that are assumed to be potentially carcinogenic. Occupational exposure to asbestos has been shown to significantly increase the risk of lung cancer in many industrial workers. The health effects of exposure to low levels of asbestos remain to be determined. Researchers also continue to investigate the effects of a number of compounds including asbestos, paint dust, silica, man-made fibers, welding fumes, and polycyclic aromatic hydrocarbons (PAHs).
Detection. Although lung cancer is often detected on chest x-rays taken for other reasons, studies have shown that routine screening in asymptomatic smokers does not reduce mortality. Currently, the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is testing the value of routine chest x-ray in a randomized, controlled study. In order to detect pre-malignant changes and diagnose lung cancer in early stages, researchers have identified a number of genetic and biological markers in blood and sputum.
Abnormal DNA Methylation as a Marker for Early Lung Cancer. Risk assessment and early detection are particularly important goals in the management of lung cancer. One goal is to identify molecular markers that can be readily detected in available blood or sputum samples. In a collaborative study over the past year, SPORE (Specialized Program of Research Excellence) investigators at the Johns Hopkins University demonstrated their capability to detect abnormally methylated DNA in a cell-cycle gene called p16. They showed that in humans high methylation of this gene, a change at the molecular level, is an early event in the development of lung cancer. Use of the marker gene to identify early lung cancer and to detect cell changes leading to cancer appears extremely promising.
Sputum Biomarker hnRNP A2/B1. A recent study evaluated the accuracy of a new epithelial biomarker of early lung cancer by examination of expression of a tumor-associated antigen in exfoliated sputum epithelial cells. Expression of this protein, hnRNP A2/B1, identified 74 percent of early lung cancers while standard clinical screening methods detected only 21 percent (for routine cytology) and 42 percent (for chest x-ray). Detection of this protein may be a good initial screening test for lung carcinogenesis, particularly if it can be coupled in the future with markers having greater specificity. Other markers under active study include 3p, 9p, and 17q deletions.
Bronchial Biopsy. Recent studies by SPORE investigators at the University of Texas Southwestern Medical Center have revealed that DNA alterations consistent with clones of molecularly altered cells are present in the bronchial epithelium of most current and former smokers, and may persist for many years after smoking cessation. These findings indicate that molecular studies of respiratory epithelium may be useful in smokers for assessing the risk of developing invasive lung cancer and for monitoring response to chemoprevention.
Treatment
Photofrin. In January, the Food and Drug Administration approved the use of Photofrin, a light activated drug for use in photodynamic therapy for patients with microinvasive lung cancer who are not eligible for surgery or radiotherapy. The drug received approval earlier for palliative treatment of certain cancers, but this was the first North American approval of the therapy for a potentially curative use. It was previously approved in Japan and Germany for early stage lung cancer treatment.
Control
Tobacco Research Implementation Group (TRIG). The Tobacco Research Implementation Group (TRIG) was created to establish the NCI's tobacco-related cancer research priorities for the next five to seven years aimed at reducing morbidity and mortality caused by tobacco use. These priorities are described in a new report, "The National Cancer Institute Tobacco Research Implementation Plan, Priorities for Tobacco Research Beyond the Year 2000", was released in November 1998. This report outlined nine overarching opportunities for tobacco-related cancer research, including the establishment of Transdisciplinary Tobacco Research Centers and Community Tobacco Control Interventions. The text of the TRIG report is available on line at http://dccps.nci.nih.gov/tcrb/TRIP/.
Two of these recommendations are now being implemented. These new initiatives will alter the way tobacco control research has been traditionally conducted. Interdisciplinary Tobacco Use Research Centers will take advantage of advances in molecular biology, genetics, and behavioral science to study the tobacco problem in ways that will integrate biological and psychosocial models of tobacco and addiction. To facilitate advances, the NCI and the National Institute of Drug Abuse are supporting new research centers that will use new models of research organization, synthesis, and collaboration. The second major new program, Research in State and Community Tobacco Control Implementation, will look at policies that influence behavior, including excise taxes, advertising restrictions, clean indoor air policies, and restrictions on tobacco sales to minors. They will also examine, for example, the impact of large media campaigns and how they influence sub-populations such as heavy smokers and youth.
Smoking. Smoking is known to be the most significant risk factor for lung cancer. Lung cancer mortality rates are about 13 times higher for current female smokers compared to 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. Although smoking prevalence among women 18 and older declined from 1991 to 1995, the percentage of high school students who smoke frequently 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. The NCI, with other NIH Institutes, issued a recent request for applications (R.A.) on prevention and cessation of tobacco use by children and youth in order to reduce national tobacco use prevalence rates and accompanying tobacco-related disease rates and economic costs.
Nicotine Addiction. Several groups of scientists have been investigating 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 genes that regulate the actions of dopamine (a neurotransmitter in the brain) may influence smoking behavior. The regulating effect that nicotine has on dopamine can induce a feeling of pleasure in smokers. Consequently, individuals suffering from depression, attention deficit disorder and eating disorders commonly "self-medicate" with nicotine. Greater knowledge of how these genes influence nicotine dependency 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 carried a specific variation in their dopamine receptor gene and were less likely to be smokers, or, if they smoked, 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 currently being a smoker, and the length of periods of smoking abstinence. This information suggests that it is possible to develop new drug therapies targeted toward helping people stop using tobacco.
ASSIST. In collaboration with the American Cancer Society, the NCI is conducting the American Stop Smoking Intervention Study (ASSIST), which provides funds to state health departments to support a variety of public and private community organizations that seek to reduce tobacco use. The data show that between 1993, when the program began, and early 1996, per capita cigarette consumption in the 17 ASSIST states fell 7 percent as compared to nonparticipating U.S. states. As a result of findings from ASSIST and other studies, plans are now under way to implement comprehensive tobacco control programs in all 50 states.
Culturally specific smoking cessation initiatives. In a four year study conducted among low income African Americans in a community health center in Durham, NC, a group of smokers received tailored print materials (birthday cards and newsletters) in addition to physician messages to encourage smoking cessation. The print materials were developed by the NCI to meet the needs of individual smokers to help them overcome their individual barriers to smoking cessation. Smokers who received these materials were three times as likely as those who did not receive them to have stopped smoking. These new kinds of interventions are now being tested in several parts of the country by different researchers and offer new hope that smokers, especially those who are thinking about quitting, may be helped by low intensity, cost-effective interventions.
(Keywords: adenomatous polyposis coli, APC, beta-catenin, colonoscopy, detection, diet and exercise, fecal occult blood testing, flexible sigmoidoscopy, HCAs, Hereditary Nonpolyposis Colorectal Cancer, heterocyclic amines, hMSH2, hMLH1, hPMS1, hPMS2, HNPCC, hormone replacement, microsatellite mutator phenotype, MMP, non-steroidal anti-inflammatory drugs, NSAIDs, PAHs, polycyclic aromatic hydrocarbons, smoking, treatment, vitamin D)
Cancer of the colon and rectum accounted for approximately 67,000 cancer cases and 28,600 deaths in American women in 1998. Currently colorectal cancer is the third leading cause of cancer death among women.
HNPCC. In 1998, an NCI working group on Hereditary Nonpolyposis Colorectal Cancer syndrome (HNPCC) developed the "Bethesda Guidelines" for testing of colorectal tumors for microsatellite instability. These guidelines may help identify cases of HNPCC, which currently accounts for a large proportion of hereditary colorectal cancers and affects as many as 1 in 200 individuals in industrialized nations. In HNPCC families, any one of four genes, hMSH2, hMLH1, hPMS1 and hPMS2, are known to be defective. These genes encode components of a DNA repair complex that act in concert as "proofreaders" to repair damaged DNA. Loss of this DNA mismatch repair system results in an increased mutation rate that contributes to the development of cancer. Individuals within HNPCC families who inherit one of these altered genes have an 80-90 percent lifetime risk of developing one or more colon cancers. Research on these genes in human cells and model systems will increase knowledge of the mechanism(s) by which these mutations lead to the accumulation of genetic errors which result in cancer initiation.
MMP. Another phenomenon, known as the microsatellite mutator phenotype (MMP), cripples the cell's ability to repair DNA damage leading to a cascade of additional mutations. In MMP, one of the mismatch repair genes itself contains a mutation that disables the gene's function. In the case of colorectal cancer, tumors with MMP differ slightly from other colorectal tumors and thus research is under way to determine whether patients with MMP would benefit from new treatment modalities.
NCI-supported scientists recently demonstrated one of the pathways by which MMP leads to human cancer. Normally, signals for programmed cell death are sent to a cell with highly mutated DNA. The BAX gene is involved in this process, controlling cell growth and programmed cell death. Cells that have lost the function of the BAX gene, however do not respond to the death signal, but continue to grow as a cancer. It now appears that human cancers resulting from MMP each arise from the inactivation of different growth control genes.
This basic knowledge is an exciting breakthrough in understanding the mechanisms of cancer development, as well as an important research tool for learning more about tumor progression. The most immediate clinical application is the ability to develop genetic tests to alert individuals who are genetically susceptible to colorectal cancer. This knowledge may also help predict whether a given cancer will respond to certain drugs.
APC and Beta-catenin. For several years, scientists have known that mutations in the adenomatous polyposis coli (APC) gene are responsible for both a familial form of colon cancer that arises in young adults and sporadic forms of the disease in older individuals. Researchers have been gathering important clues about the APC protein's function by examining its interaction with other cellular proteins, and especially its interaction with beta-catenin. New findings suggest that disrupting APC's regulatory control of the beta-catenin-Tcf complex is a crucial and early event in the transformation of colon cells from their normal state to malignancy. Scientists now face the challenge of identifying the genes that are activated by the beta-catenin-Tcf complexes and inhibited by APC. Such knowledge can have important implications for treatment of colon cancer by providing an important target for chemotherapeutic agents.
Smoking. Most case control studies of cigarette smoking and adenomas have found an elevated risk for smokers. A large population-based case control study supports the view that current tobacco use and tobacco use within the last 10 years is associated with colon cancer. A 50 percent increase in risk was associated with smoking more than a pack a day relative to never smoking. Additionally, increased mortality from colorectal cancer was associated with a history of smoking. The high male-to-female mortality ratio for colorectal cancer incidence and mortality over the latter half of this century in the United States may have been the result of tobacco use by men earlier in the century. Increased rates of smoking among young women may predict equal mortality rates from colorectal cancer in the twenty-first century.
PAH and HCAs. Current reports suggest that certain chemicals may play a role in the development of colon cancer. Polycyclic aromatic hydrocarbons (PAH) are believed to cause gastrointestinal tract cancers, either directly as carcinogens or indirectly through the induction of enzymes that activate other potential carcinogens such as heterocyclic amines (HCA). The NCI has conducted significant developmental work on methods for studying these potentially carcinogenic compounds that are formed when meat is cooked at high temperatures. To clarify the role of these carcinogens, NCI researchers have developed a database on cooking methods and their associated levels of PAHs and HCAs, and a food frequency questionnaire, both of which have greatly improved methods of dietary assessment for cooked meat, PAHs and HCAs. The database and questionnaire have been used to investigate the role of meat intake and HCA exposure in the development of colorectal adenomas, lung, breast, and prostate cancers. A 2.4 fold increased risk of colorectal adenomas was found for people consuming well-done red meat when comparing the top and lowest quartiles.
Detection. Annual or biennial fecal occult blood test screening in people age 50-80 has been shown to decrease mortality from colorectal cancer. Regular screening by sigmoidoscopy in people over the age of 50 may decrease mortality from colorectal cancer, but there is insufficient evidence to determine the optimal interval for such screening. Other screening studies published during the past year have refined knowledge about how these screening tests detect early cancer and polyps and assess factors that influence compliance with screening recommendations. As part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), the NCI is supporting several research projects and clinical trials of CT colonoscopy ("virtual colonoscopy") to determine its value in screening.
Diet and Exercise. 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. Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake. Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance. Most animal and epidemiologic studies show a protective effect of dietary fiber on colon carcinogenesis. However, it has been suggested that the inverse association with fiber may be reflective of some other closely associated dietary constituents, such as the anticarcinogens found in vegetables, fruits, legumes, nuts, and grains. Alcohol consumption and a sedentary lifestyle have been associated in some, but not all, studies with an increased risk of colorectal cancer.
Vitamin D. Vitamin D may play a protective role in large bowel cancer. According to the results of a recent study that used serum levels of vitamin D metabolites as measures of vitamin D exposure, the relative risk among persons with the greatest vitamin D exposure was 70% lower than persons with the lowest level of vitamin D exposure. In the future, vitamin D supplements may be recommended for individuals at high risk of colorectal cancer.
Hormone Replacement. The hypothesis that sex hormones may influence colorectal cancer risk was formulated in the early 1980s, but epidemiological studies of a relationship between colorectal cancer risk and hormone replacement therapy (HRT) and oral contraceptives (OC) have only accumulated data over the last few years. Several large studies have reported a reduced risk of colorectal cancer among HRT and OC users; however, other studies have given inconsistent results. Thus, the association of colorectal cancer with reproductive and menstrual factors is neither strong nor consistent and requires further study.
NSAIDs. In contrast, the association between non-steroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer is extremely significant. Animal and human studies have clearly 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 reduce the risk of colorectal cancer by 40 to 50 percent 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. Research has shown that in patients with moderately advanced disease, treatment with the anti-cancer drugs fluorouracil (5-FU) and levamisole after surgery leads to a 33 percent reduction in mortality over surgery alone. According to more recent findings, six months of treatment with 5-FU and leucovorin after surgery is equivalent to one year of 5-FU/levamisole treatment in mortality reduction. Research is now concentrated on whether markers can be found to identify patients who are likely to benefit from adjuvant treatment, as well as on the development of newer agents (such as CPT-11 and oxaliplatin) in combination with 5-FU and leucovorin for use in metastatic disease as well as in adjuvant therapy.
(Keywords: AIDS-associated malignancies, anal cancer, biology, cervical cancer, HPV, human papilloma virus, Kaposi's sarcoma, KS, mother-to-child transmission, non-Hodgkin's lymphoma, prevalence, treatment)
Prevalence. AIDS continues to be a major public health concern. A recent analysis of trendsin HIV incidence among young adults in the United States found a striking drop in the spread of HIV infection in young men through homosexual contact and injected drug use in the early 1990s, with 50 percent fewer White men aged 18 to 27 living with HIV infection in 1993 than in 1988. In contrast, the number of young minority men with the infection was roughly the same in 1988 and 1993. And the rate of heterosexual transmission of HIV infection in young women rose more than 60% from 1988 to 1993.
HIV infection and/or AIDS is approximately 10-fold more common in African American women and 5-fold more common in Hispanic American women than in White American women. Researchers are now studying genetic determinants in the major histocompatibility complex, in chemokines and chemokine receptors, and in other genes in HIV-1 infected African American and Hispanic populations. These studies may identify individuals at risk for rapid disease progression who may benefit from early therapeutic intervention.
Mother-to-child Transmission. Intensive work continues toward understanding mother to child transmission of HIV, which has a high incidence in African American and Hispanic American populations. A clinical trial of 7,000 Malawi women revealed that simple cleaning of the birth canal during delivery greatly reduced deaths and serious bacterial infections in both mothers and infants, but did not reduce HIV transmission. Data from the NCI and National Institute of Child Health and Human Development, collaborative Mothers and Infants Cohort Study, conducted in New York City in a predominantly African American/Hispanic American population, show that HIV transmission from mother to child is increased for HIV+ mothers who had a high "HIV viral load" or who had frequent intercourse or illicit drug injection during the third trimester of pregnancy. Current studies are focused on further evaluation of these observations.
Biology. Researchers in several institutions, including NCI, have found that the CKR5 gene is of critical importance to a patient's progression from HIV infection to AIDS — or even to an individual's risk of becoming infected. CKR5 codes for a cell surface protein that is a required entry port for HIV infection of macrophages and monocytes, the principal cell type in which HIV enters and persists in infected people. Everyone inherits two copies of CKR5 — one from each parent. About 20 percent of Whites inherit one normal copy of the gene and one copy that is mutated in such a way that its function is destroyed. Although these individuals are susceptible to HIV infection, they progress to AIDS more slowly than those with two normal CKR5 genes. Approximately 1 percent of Whites inherit two mutated copies of CKR5; these individuals are, for all practical purposes, genetically immune to HIV infection, even when heavily exposed. Recent NCI research has estimated the date of the emergence of this mutation to around 500 years ago.
The vast majority of long term nonprogressors, however, cannot be attributed to presence of these mutations, suggesting that there are other important resistance factors. One such factor may be the level of CKR5 expression on cell surfaces, which may have a direct influence on HIV-1 infection. Research on this and other, similar factors is ongoing. NCI researchers have been examining the relationship between HIV infection and AIDS progression with natural human genetic variations (polymorphisms).
AIDS-Associated Malignancies.AIDS-associated malignancies are emerging as an epidemic within the larger AIDS epidemic. An estimated 40 percent of all AIDS patients may eventually develop Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, or one of the other malignancies associated with AIDS such as cervical cancer or anal cancer. Although KS is extremely rare among women, non-Hodgkin's lymphoma currently ranks sixth in overall female cancer incidence and mortality. Furthermore, cervical neoplasia is five times more likely 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 research resources that receive NCI AIDS 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 U.S. for the purpose of 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. In spite of new combination therapies designed for the treatment of HIV-infected individuals, drug resistant viral mutants continue to thwart even the best regimens. Therefore, development of a vaccine against HIV remains an important public health priority for controlling the spread of AIDS. A variety of live and attenuated HIV-recombinant vaccine approaches are under investigation. One promising approach is the use of adenoviruses, which infect epithelial cells of the upper respiratory tract and are best known for causing the common cold, as vehicles to "carry" the vaccine to the cells.
REQUESTS FOR APPLICATIONS (RFAS)
AND
PROGRAM ANNOUNCEMENTS (PAS)
RELEVANT TO WOMEN'S HEALTH - FY1997-1998
R.A. DE-97-003
NIDR, NINR, NIDA, NCI & ORWH
Sex and Gender-Related Differences in Pain and Analgesic
Response The purpose is to identify significant sex- or
gender- related differences in analgesic response and to
characterize fundamental biological or biobehavioral
mechanisms underlying male/female differences in response to
nociceptive stimuli or clinical pain. Both animal and human
studies are encouraged. This initiative is expected to yield
new insights that may ultimately lead to more targeted,
effective, and safe approaches for treating acute or chronic
clinical pain and preventing pain-related disability in both
men and women.
R.A. CA-97-005
R.A.
CA-98-012
Chemoprevention in Genetically Identified High Risk
Groups The purpose of this initiative is to establish
integrated, multidisciplinary research programs that define
and evaluate chemopreventive strategies in asymptomatic
subjects at high risk for cancer.
R.A. CA-97-010 (NCI, NICHD, & NINR)
R.A. CA-98-002
(NCI, NICHD, NIDA, NIDR, NIMH, & NINR)
Prevention of Tobacco Use by Children and Youth in the
U.S. The purpose is to conduct research that has clear
implications for the immediate and significant reduction of
tobacco use by children and youth in the United
States.
R.A. CA-97-016
R.A.
CA-98-021
Minority-Based Community Clinical Oncology Program The
purpose is to support as a national resource those
physicians involved in the care of minority cancer patients
in the NCI clinical trials program The linkage of minority
cancer patients to the current clinical trials network will
also facilitate the transfer of new technology in treatment
and cancer prevention and control practices to minority
communities and their physicians.
R.A.
CA-97-017
Cancer Research Networks Across Health Care Systems The
purpose is to encourage the expansion of collaborative
cancer research among health care provider organizations
that are oriented to community care, have access to large,
stable and diverse patient populations and are able to take
advantage of existing integrated databases that can provide
patient-level information relevant to research studies on
cancer control and cancer-related population
studies.
R.A.
CA-97-022
Information for Breast and Colon Cancer Cooperative Family
Registries The purpose is to create registries that
represent an interdisciplinary consortium of participating
centers of excellence in clinical and human genetics and
epidemiology. The Registries, funded as cooperative
agreements, serve as a research infrastructure by linking
the collective scientific expertise of the collaborating
centers with study populations through a central registry of
participating families, and providing access to scientific
expertise beyond the scope of a single institution or
organization.
PA-97-105
(NIAID, NICHD, NCI, NIDR, NIDDK, NINDS & ORWH)
HIV Pathogenesis in Women's Interagency HIV Study The
purpose is to encourage highly focused basic research
integrated with the Women's Interagency HIV Study (WIHS)
scope and structure. Applications are expected to utilize
the WIHS study population, a large cohort of HIV-infected
women in the U.S., to formulate specific hypotheses
concerning HIV/AIDS pathogenesis in women.
PA-97-055 (NCI,
NIDR)
Priorities in Behavioral Research in Cancer Prevention and
Control The purpose is to address behavioral research
issues in cancer prevention and control. This Program
Announcement addresses recommendations made by a special
Behavioral Research in Cancer Prevention and Control Working
Group in 1996, which consisted of leading national experts
whose role was to identify behavioral research needs in
cancer prevention and control during the coming
years.
PA
CA-97-057
Epidemiology of AIDS/Retroviral-Associated Cancers The
purpose is to better understand the occurrence and molecular
epidemiology of pre-neoplastic conditions and cancers that
occur within the contexts of underlying infection with human
retroviruses such as HIV/AIDS, non-infectious causes of
immunosuppression such as organ transplantation, or
subsequent to anti- retroviral therapies, particularly
zidovudine and other nucleoside reverse transcriptase
inhibitors.
PA
CA-97-109
Clinical Epidemiologic Studies in Hereditary Breast/Ovarian
Cancer The purpose is to encourage innovative
epidemiologic studies that address clinical issues facing
women with inherited predisposition for breast and/or
ovarian cancer. This initiative seeks to enhance informed
decision-making among women at hereditary cancer risk by
strengthening and expanding the scientific knowledge about
preventive and therapeutic options.
PAR-97-027 (NCI, NHLBI, NIAID, NICHD, NIDA, & NIMH)
PAR-98-043
(NCI, NHLBI, NIAID, NICHD, NIDA, & NIMH)
Centers for AIDS Research The purpose is to support
Centers for AIDS Research (CFARs). CFAR cores provide
infrastructure and promote basic, clinical, behavioral and
translational AIDS research activities at institutions that
receive significant AIDS funding from multiple NIH
Institutes or Centers.
R.A.
CA-98-008
Specialized Programs of Research Excellence in Ovarian
Cancer SPOREs are programs that focus on translational
research (research designed to move laboratory discoveries
into patient and population research settings). SPORE
institutions conduct high-quality research on the
prevention, etiology, screening, diagnosis, and treatment of
cancer; and are encouraged to conduct rehabilitation and
quality-of-life research. It is anticipated that at least
one Ovarian Cancer SPORE will be awarded in
FY1999.
R.A.
CA-98-010
AIDS-Associated Malignancies Clinical Trials Consortium
The purpose is to conceive, create, and evaluate new
approaches to therapy of AIDS-associated malignancies.
Institutions are invited to participate or to continue to
participate in the activities of the AIDS-associated
Malignancies Clinical Trials Consortium (AMC), which has
designed, developed and performed clinical trials using
novel agents or innovative approaches in patients with
AIDS-associated malignancies for the past three
years.
R.A.
CA-98-014
Health Communications in Cancer ControlThe purpose is to
expand health communications in cancer control. Research
grant applications may include: (1) research on the use of
"new media" (interactive digital media) in cancer prevention
and control, message development including, but not limited
to, their impact on primary and secondary cancer prevention
and on cancer-related decisions and (2) refinement and
evaluation of communications systems to deliver cancer
control-related information.
R.A.
CA-98-015
Basic Bio-Behavioral Research on Cancer Related
Behaviors The purpose is to investigate the
bio-behavioral basis of cancer-related behaviors, especially
those that increase cancer risk. The NCI seeks proposals
that are novel, hypothesis driven, and utilize
pre-intervention research designs in human
populations.
R.A. CA-98-017
(NCI, NIEHS)
Regional Variation in Breast Cancer Rates in the U.S.
The purpose is to conduct epidemiologic studies to better
understand determinants of regional variations in breast
cancer incidence and mortality rates in the U.S. Studies
should take known risk factors into consideration and
utilize biological markers or indicators, e.g., of exogenous
exposures, individual susceptibility to environmental
factors, intrinsic physiological processes or risk-related
behavior, for elucidating the role of geographic-specific
elements in the natural history and progression of breast
cancer. The ultimate objective is to gain knowledge that
could lead to effective prevention and cancer control
strategies.
R.A.
CA-98-025
Breast Cancer Surveillance Consortium Expansion The
purpose is to broaden the current Breast Cancer Surveillance
Consortium research effort in several key aspects, while
continuing to support the central goals and objectives. In
addition to funding sites to collect data relevant to
mammography performance, this R.A. will also support a
Statistical Coordinating Center (SCC) to develop data
comparability processes, to serve as the central repository
for pooled data and to provide the research expertise on
complex statistical issues for analysis of these pooled
data.
R.A. CA-98-029
(NCI, NIDA)
Transdisciplinary Tobacco Use Research Centers The
purpose is to develop a Specialized Program of Research
Excellence (SPORE) in tobacco use research. The initiative
will provide support for the creation of transdisciplinary
tobacco use research centers (TTURCs).
PAS-98-040
(NIAID, NICHD, NCI, NHLBI, NIDDK, & NIA)
Opportunities in AIDS Research Grant Program: Human
Immunology The purpose is to encourage novel and
innovative research in human immunology aimed at enhancing
our understanding of the behavior of the human immune system
and the biology of human lymphocyte populations. The
emphasis of this program is on supporting human immunology
research projects that show clear promise for advancing the
basic understanding of the development and functioning of
the immune system needed to more rationally approach immune
reconstitution in HIV-infected subjects during infection and
in the period after introduction of effective antiviral
therapy.
PAR-98-096
(NCI, NHLBI, & NEI)
Therapeutic Modulation of Angiogenesis in Disease The
purpose is to encourage the translation of basic knowledge
of the angiogenic process into therapeutic applications. It
may also promote new collaborations between basic and
clinical scientists currently engaged in this area of
research to design novel therapeutic approaches to
disease.
PA-98-091
(NIAID, NCI, NCRR, NICHD, NIDR, NIDDK, & NIMH)
Mechanisms of AIDS Pathogenesis: Collaborative Teams The
purpose is to solicit hypothesis-driven in vivo HIV and AIDS
pathogenesis research by collaborative multidisciplinary
research teams. In vivo research includes studies of human
clinical or epidemiological cohorts, studies of animal
models, or studies of appropriate specimens from humans or
animals.
PA-98-102
(NINDS, NIDR, NCI, NIA, NIAID, NIAMS, NIDCD, NIDA, NIGMS,
NINR & ORWH)
New Directions in Pain Research The purpose is to study
mechanisms underlying analgesic response and pain to advance
the development of novel pain interventions, treatments and
management strategies. This PA encourages researchers to
examine the pain experience at all levels of analysis from
the gene, molecule, cell, tissue, and organ, to the
individual, family and community, with the ultimate goal of
developing new insights into pain intervention, treatment
and management.
PA CA-98-095
(NCI, NIEHS)
Genetic Regulation of Susceptibility to Tobacco-Related
Carcinogenesis The purpose is to stimulate the
investigation, at the basic experimental level, of the
mechanism of differential genetic susceptibility to
tobacco-related carcinogenesis in the context of lung cancer
and other tobacco-related cancers. The classes of
carcinogenic compounds of interest found in tobacco and
smoke include the aromatic amines, nitrosamines and
polycyclic aromatic hydrocarbons.
PA
CA-98-029
Molecular and Cellular Biology of Metastatic Tumor Cells
The purpose is to study the molecular and cellular biology
of metastatic tumor cells. This special initiative is
designed to promote collaborations and facilitate scientific
interchange between investigators, one with experience in
the biology of metastasis and the other in a more basic
scientific discipline such as molecular or cellular biology,
or biochemistry.
PA
CA-98-028
Diet, Lifestyle and Cancer in U.S. Special Populations
The purpose is to elucidate causes of cancer and means of
prevention in African Americans, American Indians, Alaska
Natives, Asian and Pacific Islanders, Native Hawaiians,
Hispanics, rural, older, low income and low-literacy groups.
These groups experience unusually high cancer incidence and
mortality for some cancer sites.
PA
CA-98-027
Cancer Survivorship Studies in Established Epidemiologic
Cohorts The purpose is to address issues related to
long-term survivorship of cancer, particularly in the areas
of specific health or lifestyle outcomes and their
modulation by common risk factors or other exposures. This
initiative seeks to build on existing resources from
previous epidemiologic studies through the application of
these new technologies, to enhance knowledge and
understanding of long-term cancer survivorship.
Second Annual Meeting of the Cancer Cube (12/8-9/96; the Cancer Cube focused on the role of estrogens in carcinogenesis)
Prophylactic Mastectomy Meeting (1/13/97)
NIH Consensus Development Conference on Breast Cancer Screening for Women Ages 40-49 (1/21-23/97)
NCI Breast Cancer Progress Review Group Roundtable (Baltimore, MD, 9/14-16/98)
16th Annual Papillomavirus Conference (Siena, Italy, 9/5-12/97; NCI listed as co-sponsor)
Strategic Planning Conference on Ovarian Cancer Research (Bethesda, MD, 12/8-9,1997; NCI, Society of Gynecologic Oncologists, Office of Women's Health, PHS)
Psychological and Behavioral Responses to BRCA Testing: A Look Below the Surface (3/6/98)
Estrogens as Endogenous Carcinogens in the Breast and Prostate Chantilly, Virginia (3/16-17/98)
International Conference on Women's Health: Occupation, Cancer, and Reproduction Reykjavik, Iceland (5/14-16/98; NCI listed as co-sponsor)
Network for Cancer Control Research Among American Indian and Alaska Native Populations (5/28-30/98)
Breast Cancer Prevention Trial: Results (Teleconference) (9/14/98)
National
Clinical Trials and Asian American Women Summit
(10/9/98)
