Prepared for: Office of Research on Women's Health, National Institutes of Health

Prepared by: National Cancer Institute, Office of Science Policy, Planning,
Evaluation, and Analysis Branch

Submitted: February 28, 1997

INTRODUCTION

Cancer is the leading cause of death for women who are between 35 and 50 years of age, and it remains the second leading cause of death among all women in the United States. In 1997, approximately 265,900 women are expected to die from cancer, including 162,800 from cancers of the lung, breast, colon and rectum, and reproductive tract (cervix, uterus, and ovary). Despite this high toll, the overall number of cancer deaths are finally declining.

New findings from two independent but complementary studies, conducted by the National Cancer Institute and academic researchers, show that the percentage of the U.S. population that dies from cancer each year fell by nearly 3% between 1991 and 1995, the first sustained decline since national record-keeping was instituted in the 1930s.

Most of the overall drop in the death rate is due to declines in breast, colorectal, and gynecologic cancer deaths in women and lung, colorectal, and prostate cancer deaths in men. Furthermore, the decline in cancer mortality has been greatest among African Americans, although rates remain significantly higher among this group than among white Americans.

In the short term, this decline means that 16,000 more Americans will survive cancer this year. This encouraging trend is attributable in large measure to the decrease in smoking, although reductions in drinking, exposure to the sun, and exposures to chemicals in the workplace have also played a role. In addition, cancer survival rates have improved due to better early detection methods and advances in treatment. The increasing number of cancer survivors, though, has provided a new challenge – determining how best to serve the needs of over 10 million cancer survivors with over 7 million of those being long-term survivors. NCI has met this challenge head-on through the establishment of the Office of Cancer Survivorship which will explore the physical, psychological, and economic well-being of survivors. The office will support research covering the spectrum of issues facing cancer survivors including long-term medical and psychosocial effects of treatment, factors that predispose survivors to second malignancies, reproductive problems following treatment, and insurance/employment issues.

NCI is committed to continuing efforts to reduce the toll of cancer through targeted research. NCI supports a comprehensive and coordinated cancer research program that investigates all aspects of cancer including biology, risk, interventions, and control.

This report will address the accomplishments of NCI's cancer research program, during fiscal years 1995 and 1996, regarding cancers specific to or primarily affecting women or those with high incidence or mortality for women.

CANCERS SPECIFIC TO OR PRIMARILY AFFECTING WOMEN

I. Breast Cancer

Breast cancer is the second leading cause of cancer death in women, and accounts for about 30% of all female cancers with 180,200 new cases and 43,900 deaths from breast cancer estimated for 1997. In addition, 1,400 men will develop breast cancer and about 290 will die from the disease. However, as NCI announced in May 1996, the breast cancer death rate for American women is declining. This announcement was based on data available from 1989 through 1993. In both white and black women, the greatest improvements in mortality were seen in younger age groups. This finding suggests that improved breast cancer management from early detection to treatment is effective.

Despite this good news, there is still much breast cancer research to be done. To optimize our efforts, NCI plans to establish a Progress Review Group (PRG) to assess research opportunities in breast cancer and the activities of NCI in the context of these opportunities. The Breast Cancer PRG will work with NCI staff in conducting an evaluation of the current state-of-knowledge in this area and make recommendations on how the Institute can optimally respond to and stimulate breast cancer research opportunities. This exercise will help set the NCI's research agenda in breast cancer by identifying and prioritizing those scientific opportunities that are most likely to expand our knowledge and ultimately reduce the burden of breast cancer.

1. Biology

   BRCA1 Gene. For years, scientists suspected a hereditary basis for some breast cancers. In 1994, researchers, supported in part by NCI, confirmed this belief with the discovery of BRCA1, a breast cancer susceptibility gene on chromosome 17. Scientists found that in high-risk families, women who carry mutations in BRCA1 have an 80% to 90% lifetime risk of breast cancer, and a 40% to 50% risk of ovarian cancer.

   Then, in 1995, NCI-supported scientists, in collaboration with researchers from the National Center for Human Genome Research and the extramural community, discovered a specific mutation in the BRCA1 gene (185delAG). This mutation appeared in nearly 1% of blood samples collected from women of Ashkenazi (Eastern European) Jewish descent. This finding provided the first evidence that an alteration in the BRCA1 gene is present in measurable levels not only in high-risk families, but also in a subgroup of the general population. Based on available epidemiologic data, it is estimated that the mutation may account for as much as 16% of breast and 39% of ovarian cancers in Ashkenazi Jewish women age 50 and under.

   Following this discovery NCI launched a "snapshot" study in the Washington, D.C. area. The purpose is to determine whether women who have this genetic mutation, but no family history of breast cancer, have an increased risk of developing breast and/or ovarian cancer. Results of this study, expected in early 1997, will provide essential information for genetic counseling of individuals with this specific alteration in the BRCA1 gene.

   Other studies regarding BRCA1 have yielded a wealth of information covering various aspects of the gene's function. These studies have shown that:

   • Only 10% of non-inherited breast and ovarian cancers have been linked to BRCA1 as opposed to 45% of inherited breast cancer and 80% of families with breast and ovarian cancers. Recent studies have identified the BRCA1 gene product in both normal cells and tumors cells taken from tissues other than breast and ovary. In all of these cells the BRCA1 product was found in the normal place – the cell nucleus. However, in breast and ovarian cancer cells the BRCA1 product was found mainly in the area outside the nucleus. These findings suggest that the cell location of the BRCA1 product may be related to the development of many inherited or non-inherited breast cancers.
   • BRCA1 alterations are implicated in the cause of breast tumors in young women. In one study, NCI-supported researchers demonstrated that alterations of BRCA1 were present in approximately 10% of a group of young women with breast cancer, and that the risk of having a mutation was not limited to women with family histories of breast and/or ovarian cancer.
   • Research has shown that several common mutations in BRCA1 disrupt the direct association of the BRCA1 protein with a newly isolated protein called BARD1. How BARD1 and BRCA1 might theoretically work together to suppress breast tumors is under investigation.
   • Several studies have documented the difficulty of attributing specific risk to individual patients in cancer families with identical genetic mutations. It has been shown that independent breast cancer families, with the same BRCA1 mutations, may have different patterns of disease, including the frequency of associated ovarian cancer and ages of disease onset. For example, one family had a high rate of breast and ovarian cancers occurring at a young age, while a second family, with the same mutation, had only breast cancer appearing mostly in older women. These studies show that, as with genetic susceptibility for other diseases, the consequences of having a mutation in a cancer risk gene may be modified by other factors.

   Investigations such as these underscore the need to develop genetic screening programs and train qualified counselors. Additionally, in order to further examine genetic alterations, technological advances in genome wide analyses are needed. It is the goal of NCI's newly launched Cancer Genome Anatomy Project (CGAP) to promote the development of an infrastructure of resources, information, and technologies that will provide a platform for the creation of an index of all genes that are expressed in tumors. CGAP will start by focusing on breast, as well as ovarian, colon, lung, and prostate tumors. The project intends to identify the molecular characteristics that distinguish one kind of breast cancer from another in ways that will guide future approaches to the design and choice of effective breast cancer intervention and prevention strategies to reduce mortality.

   p53 Gene. The normal p53 gene has been found to have a tumor suppressor function in that it diverts proliferating cancer cells into a cell death pathway. When a mutation occurs, or p53's function is otherwise halted, cancers may develop. In 1995, investigators found p53 mutations in approximately 5% of benign breast lesions with no subsequent development of breast cancer. But p53 mutations were also found in 45% of benign lesions in women who later developed breast cancer during a 50 year observation period. This work suggests that what may appear as benign breast tissue may show early molecular signs of cancer. These findings will promote the development of molecular tests that can assess risk for breast cancer.

   p16 Gene. Various chromosomes have been observed to be affected by a higher number of abnormalities in breast cancer. One chromosome region that undergoes deletions in a variety of tumor types is found on the short arm of chromosome 9. Detailed analysis of this region has shown that it contains gene p16 – a gene that controls the cell cycle. Its deletion in many tumor types has suggested that p16, when functioning normally, is actually a tumor suppressor. Of the primary breast cancers analyzed, a high number showed alterations of chromosome 9. Mutational analysis of p16 suggested that p16 was not the target of the mutations and indicated the possible existence of another tumor suppressor gene on the short arm of chromosome 9 near p16.

   P16 alterations have also been connected with cell immortality, or the ability of a cell to grow unchecked. Studies are underway to determine if loss of p16 is enough for a cell to become immortal, and whether restoration of p16 function will force the cell to age normally. Knowing if p16 plays a role in determining whether a cell becomes immortal or ages, could lead to new treatments of breast, and possibly other cancers. These treatments theoretically would force precancerous cells to mature and die normally, thus halting the cancer before it starts.

   Cellular Markers. Although most women with node-negative breast cancer (cancer that has not spread to the lymph nodes) will be cured by surgery alone or surgery plus radiation, about 30% of these patients will develop metastases and die of breast cancer. Identifying patients at risk of progression would allow for better management decisions and might spare some women treatment with toxic chemotherapy. Many markers, cellular components found in a specific tissue, have been identified in breast cancer tissue. A number have been studied extensively to develop tests that might aid clinicians and patients in making decisions about treatment of early stage breast cancer.

   NCI conducted a retrospective study of over 700 specimens from women with node-negative breast cancer. The patients had been diagnosed at least eight years prior to the study and follow-up information was available on all patients. The statistical analysis included standard prognostic indicators as well as the experimental markers. The results suggest that histologic grade (an evaluation of how abnormal the cells of the tumor appear) and Ki-67 (a marker that measures how many of the tumor cells are dividing) are the strongest predictors of outcome. When both the histologic grade and the Ki-67 had low values, patients had a very high probability of a good outcome in the absence of any systemic therapy. Over 95% of these "good outcome" patients were alive with no recurrences at eight years following diagnosis and surgery.

   In addition, NCI-supported researchers began a study in 1995 to investigate whether or not the electrical potential of a breast cell undergoing carcinogenesis might serve as a cancer indicator or marker. It has been observed that the breast cell membrane electrical potential for women with ductal carcinoma is much different than the membrane potentials for women with benign lesions. This study might result in a new means of cancer diagnosis.

2. Risk

   Recognized Risk Factors. Intramural investigators in NCI's Division of Cancer Epidemiology and Genetics examined how much of the breast cancer burden can be attributed to certain recognized risk factors. Analyzing nationwide data collected on 7,508 women, investigators found that more than 40% of breast cancer may result from well-established risk factors: older age at first birth or never having children, moderate or high income, and a family history of breast cancer. When the above three risk factors are combined, they account for 40% of breast cancer cases in the United States. Other recognized risk factors (early age of menarche and prior benign breast disease), would likely further increase the percent of breast cancer explained by known risk factors. Since it is not possible to significantly alter these recognized risk factors, investigators point out the need to understand their underlying biological mechanisms in order to design intervention and prevention strategies.

   Environmental Risk. In addition to genetic and lifestyle factors, environmental factors are believed to play a role in the development of breast cancer. NCI, along with the National institute of Environmental health Sciences is continuing to support two studies of breast cancer risk and the role of environmental factors on Long Island and in the Northeast/Mid-Atlantic States, regions with reported high breast cancer rates. The Long Island Breast Cancer Study Project (LIBCSP) consists of several studies looking at risk associated with exposures to pesticides, contaminated drinking water, air pollution, electromagnetic fields, and hazardous waste, as well as occupational exposures and diet. Another aim of the LIBCSP is to develop measurement tools that can be used in investigating environmental factors in other geographic areas.

   The Northeast/Mid-Atlantic Breast Cancer Study is attempting to quantify the effects of environmental exposures such as pesticides, PCBs, electromagnetic fields, dietary components, and smoking, in association with other suspected breast cancer risks. The study is being conducted in Connecticut, Delaware, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont, and the District of Columbia.

   NCI investigators recently determined that the breast cancer mortality rates are much more uniform throughout the U.S. when regional differences in the percentages of women with established breast cancer risk factors are taken into account. However, not all of the geographic variation is accounted for by this consideration. Of particular concern to researchers is determining why the San Francisco Bay area had the highest rate of breast cancer in the world based on data from 1947 through 1992. Stanford University researchers are trying to answer this question by determining how San Francisco breast cancer rates alone compare to national rates when controlled for the prevalence of known risk factors in the Bay area.

   Fat Intake. There are still questions regarding whether or not fat intake affects a woman's risk of developing breast cancer. Previous studies showed a connection between increased fat intake and increased risk for breast cancer. However, results of pooled analyses of dietary information collected from more than 335,000 women residing in the United States, Canada, the Netherlands, and Sweden found no evidence of an association between total dietary fat intake and breast cancer risk. There was no reduction in risk among women whose dietary fat intake was less than 20% of the total energy intake.

   Similar Factors for In situ and Invasive Tumors. Although in situ breast cancer incidence has apparently increased tremendously in recent years, primarily as a result of early diagnosis with more sensitive mammographic screening, its epidemiologic profile remains undefined. A study of breast cancer in younger women showed that most risk factors for invasive cancer also applied to the in situ tumors. However, some risk factors, such as not having given birth and body mass, seemed to have a greater influence in the development of in situ tumors. These results suggest that in situ tumors are likely to be on the causal pathway of invasive tumors.

   Estrogen and Progestin Hormone Replacement Therapy. In a recently published study, it was shown that use of the combination of estrogen with progestin hormone replacement therapy (HRT) was not found to influence the risk of breast cancer in middle-aged women. Furthermore, longer duration of use of this combination (more than 8 years) was actually associated with a reduction in risk.

   Estrogen and Apoptosis. According to the results of a breast cancer tissue study, sex hormones such as estrogen can inhibit cell death (apoptosis) by increasing the production of an anti-apoptosis protein. The study examined the effect of estrogen on two proteins that modulate the process of apoptosis. One, which is an anti-apoptosis protein, had increased production in the presence of estrogen. These findings also suggest that control of apoptosis may be a mechanism by which estrogen influences breast cancer risk. Further investigation of the role of estrogen in cell death pathways could lead to the design of antitumor drugs that target this pathway.

3. Intervention

   Prevention. The National Surgical Adjuvant Breast and Bowel Project is conducting the Breast Cancer Prevention Trial (BCPT) which is examining whether or not taking Tamoxifen can prevent breast cancer in women who are at risk for the disease. Accrual for the BCPT is expected to be complete in early 1997.

   Aside from tamoxifen, the other potential breast cancer prevention agent that has undergone the most development is fenretinide. A randomized study of this agent in 3,500 breast cancer patients will address the issue of whether it can reduce second primary breast cancers. Also, a pilot chemoprevention study of fenretinide and tamoxifen in patients at high risk for developing invasive breast cancer was launched in 1996.

   Other ongoing NCI breast cancer chemoprevention trials are looking at a variety of agents and factors for the prevention of primary or secondary breast cancers. Some of the trials are looking at low-fat diet, fish oil, and soy supplements in breast cancer patients; correlation of menstrual cycle phase at time of surgery with disease-free survival, and weight loss interventions for women previously treated for breast cancer.

   Detection. NCI supports research on breast cancer detection technologies and screening mammography for all women. Development of imaging technologies with greater sensitivity and specificity than conventional mammography such as digital mammography, computer-aided diagnosis, magnetic resonance imaging, nuclear medicine, ultrasound, PET imaging, EPR imaging, and optical imaging is a priority.

   In order to produce innovations in imaging technology, NCI is collaborating with the Department of Defense and the National Aeronautics and Space Administration to design new screening technologies and translate current military and space technologies for use in high-resolution digital detection systems, computerized image enhancement, archiving and interpretation, and teleradiology.

   In September 1996, NCI and the U.S. Public Health Service Office on Women's Health sponsored a one-day briefing on "New Frontiers in Breast Cancer Imaging and Early Detection: From Missiles to Mammograms". The briefing was designed to discuss breast cancer detection technologies being explored, to show the progress made in translating imaging technologies from other fields for the improvement of early breast cancer detection, and to foster collaborations among researchers.

   To meet the mandate of the Mammography Quality Standards Act of 1992 for the evaluation of mammography programs in the community, NCI established the Breast Cancer Surveillance Consortium in 1994, with nine sites throughout the U.S. participating. By the year 2000 the database will contain information on nearly 3.2 million screening mammographic examinations and over 24,000 breast cancer cases. The database will be a resource for clinical research to study mammography screening practices in the U.S. and to compare performance across regions. These efforts should enhance understanding of mammography screening practices, improve quality of data used to evaluate the performance of mammography, and, through publication and feedback of the data to radiologists in the community, improve quality of mammography screening throughout the U.S.

   NCI began working with investigators in Great Britain in 1996 to help speed completion of a British screening trial for women 40 to 49. In 1995, in cooperation with an international group of investigators, NCI launched the first quantitative overview analysis of primary data from all screening clinical trials to date.

   The results from the overview analysis, recently completed Swedish screening trials, and other screening studies were presented at a mammography screening consensus conference held at the National Institutes of Health in January 1997. The conference panel of experts looked at new data regarding the issue of whether or not screening women between the ages of 40 and 49 reduces mortality from breast cancer. They concluded, in a consensus statement, that the scientific data available did not show a clear reduction in mortality for women screened regularly between the ages of 40 and 49, and did not "warrant a single recommendation for mammography for all women in their forties. Each woman should decide for herself whether to undergo mammography." The panel stated that, "for women in their forties who choose to have mammography performed, costs of the mammograms should be reimbursed by third-party payors or covered by health maintenance organizations."

   Later assessment of the evidence on screening by NCI's National Cancer Advisory Board led to the Board concluding that breast cancer screening for women between the ages of 40 and 49 is beneficial.

   NCI, in consultation with the advisory board, will develop materials that communicate breast cancer risk information and the benefits and limitations of mammography screening for women in different age groups.

   Treatment.

   • Tamoxifen Use – Based on results from a clinical trial done by the National Surgical Adjuvant Breast and Bowel Project (NSABP), NCI released a clinical announcement that suggests in routine clinical practice that physicians limit Tamoxifen use for the treatment of early breast cancer to 5 years. Results from the clinical trial showed no additional benefit from taking Tamoxifen for more than 5 years and raised the possibility that continued use might increase the risk of endometrial cancer. Several special studies linked to the Surveillance, Epidemiology, and End Results (SEER) Program are examining the relative risk of endometrial cancer associated with Tamoxifen use, particularly how it is related to duration of exposure.

     Also essential to the clinical announcement was the importance placed on the benefits that Tamoxifen offers, including a proven survival benefit to women with early-stage breast cancer, when Tamoxifen is taken as an additional therapy following surgery.

     Another clinical trial conducted by the NSABP was designed to see if there were any differences in outcomes between African-American and white women taking tamoxifen as an additional therapy. The study showed that there was no difference in outcomes for women from either group.

     In addition, several special studies linked to the Surveillance, Epidemiology and End Results (SEER) Program are examining the relative risk of endometrial cancer associated with tamoxifen use, particularly how it is related to duration of exposure.

   • Irradiation and Lumpectomies – A trial published in 1995 comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer provided important data supporting the use of lumpectomy in patients with stage I or II breast cancer, and demonstrated that subsequent irradiation reduces the probability of local recurrence of tumor.
   • Patterns of Care – A number of studies are using SEER data to assess patterns of care for breast cancer patients in various geographic locations. Several investigators are looking at the use of adjuvant therapy and changes in treatment over time for breast cancer. These studies will also compare treatment by geographic location. Other studies are analyzing data from SEER and existing insurance databases for the patterns of breast cancer screening and treatment among patients in a variety of health care settings. One study is assessing the relation between hormone replacement therapy and survival following breast cancer diagnosis.
   • Survival – Racial Differences – A recent study examined the ability of recognized prognostic factors for breast cancer to account for the observed poorer survival in blacks compared with their white counterparts. About 40% of the difference in survival was explained by more advanced stage of disease among blacks at time of detection, and another 15% by cellular differences. The analysis indicated that reducing the survival disadvantage for black women with breast cancer is most likely to be achieved through strategies aimed at early detection of disease, improved access to primary care and mammography, and increased use of screening.
4. Cancer Control

   World Wide Web Initiatives. NCI has launched a broad initiative with patient advocate groups to make information on clinical trials available to patients and the public on the World Wide Web. In the first phase, the National Alliance of Breast Cancer Organizations (NABCO) and NCI summarized the breast cancer clinical trials protocols found in PDQ (a database of cancer related clinical trial and treatment information for physicians) as a pilot.

   The PDQ Editorial Board continues to refine and update the PDQ statements on breast cancer for health care professionals, and patients. A prototype breast cancer resource, based on the PDQ patient statements on screening and treatment, was developed in 1996. It has multimedia components, including anatomical features of the breast, schematic drawings of breast cancer surgical approaches, and a glossary with a sound file.

   NCI's International Cancer Information Center has collaborated with the National Action Plan on Breast Cancer (NAPBC) to promote the dissemination of information on breast cancer over the Internet. Staff have also participated in NAPBC's Clinical Trials Promotion Task Force which is evaluating new ways to promote the development of Clinical Trials Registries and effective strategies for promoting the value and availability of clinical trials to women with breast cancer.

   NCI is also collaborating with the Food and Drug Administration to increase the number of breast cancer clinical trials distributed through the PDQ database. In 1996, a letter was sent to pharmaceutical companies involved in the development of anticancer drugs soliciting protocols for inclusion in the PDQ database. A follow-up telephone survey will be conducted to identify the perceived barriers to submission.

   Finally, NCI's newly established Office of Women's Health is developing a WWW homepage which will provide information for researchers, health professionals, and the public regarding NCI's Women's Health initiatives.

   Education and Outreach. NCI's Office of Cancer Communications (OCC) devotes considerable resources to developing breast cancer education programs and resources. One effort seeks to increase the percentage of women over 50 who understand the importance of regular breast cancer screening. Another is designed to increase the percentage of breast cancer patients who understand the importance and availability of state-of-the-art treatment options including clinical trials. These programs and resources are disseminated primarily through NCI's Cancer Information Service (CIS) telephone service (1-800-4-CANCER) and outreach program. The CIS telephone service provides the latest most accurate information for all cancers to patients, health professionals, and to the general public. CIS's outreach program is focused on disseminating NCI's cancer resources to minority audiences, including African-American, Hispanic, Native American, and to low literate, and visually-impaired women.

   OCC's recent breast cancer education efforts include supporting National Breast Cancer Awareness Month (NBCAM). Special emphasis was placed at both the national and regional level to reach minority audiences. NCI collaborated with the Breast Cancer Resource Committee to produce, promote, and distribute a national television and radio public service announcement (PSA) featuring actress Angela Bassett, advocating the importance of early detection and treatment of breast cancer for African-American women. To support CIS outreach efforts on the regional level, OCC developed three print PSAs, one targeting African-American women, one in Spanish, and one designed for the general public. Other materials including a bi-lingual press release and radio PSAs were also developed.

   In 1995, NCI-supported researchers in California began work with a biotechnical communications firm to develop health care programming for the Black Entertainment Television Network. The programming will focus on breast cancer among African-American women. NCI researchers are also engaged in developing and evaluating interventions designed to instruct women from a variety of ethnic and population groups about the importance of early detection and screening including: visually and hearing-impaired, Hispanic, Vietnamese, African-American, Chinese American, Korean, and urban women.

   Finally, the Appalachian Leadership Initiative on Cancer (ALIC) recently received a two-year extension to evaluate four projects targeted to the medically under-served residing in the Appalachian region of the U.S. Coalitions have been formed and one is working to promote breast cancer screening, others are working on smoking cessation, cervical cancer screening, and diet modification.

5. Research Resources – Cooperative Breast Cancer Tissue Registry

   Examples of resources developed by NCI to meet scientists' needs include the Cooperative Breast Cancer Tissue Registry (CBCTR). The CBCTR was designed to support the larger scale studies required to validate the usefulness of diagnostic and predictive markers which appear promising based on results from smaller studies. The CBCTR collection currently contains specimens from almost 5,000 cases of breast cancer. Each case contains clinical and outcome data. This collection is available for researchers to test the ability of genetic and other markers to predict survival or recurrence. An on-line database, publicly available on the World Wide Web of the Internet, allows investigators to know what specimens and data are available from the Registry.

   Additional tissue resources have been and are being developed by other NCI programs. NCI's Division of Cancer Treatment, Diagnosis, and Centers' new Resources Development Branch will coordinate NCI resources in order to assure that they serve the needs of the scientific community. The new branch plans to expand and increase the usefulness of existing tissue resources, as well as the availability of rare tissues and tissues from special populations. Public databases are being developed that will provide researchers with information about the types of specimens available from existing resources and how to obtain them. These efforts should help to build the infrastructure of biological specimen and data resources.

II. Cervical Cancer

Cervical cancer is the second most common cancer of women worldwide. However, the incidence of invasive cervical cancer has been steadily decreasing in the United States. This trend is likely due to early Pap smear detection of cervical dysplasias and preneoplastic non-invasive lesions that are surgically curable. In 1997, 14,500 women in the U.S. are expected to be diagnosed with invasive cervical cancer and 4,800 are expected to die. Cervical cancer is a particular concern for minority women in the U.S., specifically Vietnamese women who have the highest rate of incidence and African-American women who have the highest mortality rate. Worldwide, 215,000 cervical cancer deaths are expected, many of which could be prevented if the cancer were detected early, while still non-invasive.

1. Consensus Conference

   On April 3, 1996 NCI sponsored a consensus conference on cervical cancer to identify major areas of agreement on the goals for preventing and treating cervical cancer. Members of the consensus panel recommended special efforts be made to reach women who have lower rates of screening and higher rates of the disease – the uninsured; women over 65; ethnic minorities; and rural and poor women. Based on an overwhelming body of scientific evidence, the panel concluded that a principal cause of cervical cancer is the sexually transmitted human papilloma virus (HPV). There are still many research questions surrounding the issue of why only a small percentage of women infected with HPV eventually develop invasive cancer. The panel also recommended different treatment options for various stages of the disease.

2. Risk

   Although many risk factors have been implicated in cervical cancer, studies over the last 5 years show that infection with some types of human papillomavirus (HPV) is strongly associated with this cancer.

   HPV Screening. Scientists are now characterizing the molecular changes that accompany HPV infections and are exploring the use of papillomavirus antibodies in the blood as a potential screening test.

   Contributing Factors. NCI-supported investigators are conducting large population-based studies of women around the world to define the full spectrum of viral (including simultaneous infections with Herpes and HIV), immunologic, hormonal, and lifestyle factors that contribute to development of cervical cancer. Such studies will identify women who might benefit from prevention trials with promising drugs such as retinoids and folic acid.

   Also, studies using SEER data are assessing the association between carcinoma in situ, treatment regiman, and subsequent pregnancy outcomes. The objective is to determine whether pregnancy outcome and method of delivery are influenced by a history of carcinoma in situ, diagnostic procedures, or treatment.

   HPV Vaccine Development. Several studies have demonstrated significant progress toward the development of a vaccine. An effective HPV vaccine would be a giant step toward cervical cancer prevention. NCI scientists, in collaboration with investigators at Beatson Institute in Scotland, have found that certain substances identified as virus-like particles (VLP) can be used as a vaccine to protect against infection by generating protective antibodies.

   Other research suggests that a vaccine for protection against one of the high risk HPV types will probably protect against most strains of that virus type. While there are numerous types of HPV, four types are most commonly found in cervical cancer; therefore, a single vaccine that provides protection against those four types could prevent more than 80% of cervical cancers. Based upon these encouraging findings, it is likely that human trials of a VLP-based vaccine will begin in the near future.

   Another kind of HPV vaccine has already been developed by researchers in the United Kingdom. The vaccine, a vaccinia virus vaccine, was created using recombinant DNA technology, a way to engineer a "crippled" virus that will deliver its altered DNA to the cells causing the host to mount an immune system attack against HPV. NCI and the UK researchers are now co-sponsoring a trial, launched May 1996, at the University of Wales, to investigate the effectiveness of this vaccine as a treatment for patients with advanced or recurrent disease.

   Estrogen and HPV. High-risk human papilloma viruses, such as type 16, are associated with over 80% of cervical cancers. Infection by HPV-16 alone may not be enough to cause cervical cancer; other factors are likely necessary. So scientists have developed an animal model to see if one co-factor associated with HPV abnormalities, long-term estrogen treatment, induces the development of cervical and vaginal cancers in mice with HPV-16. These studies show a novel mechanism of cooperation between long-term estrogen exposure and HPV oncogenes that results in cancer in the female reproductive tract of mice infected with HPV-16. Hopefully this work will lead to studies that will determine if a similar novel mechanism is at work in women.

3. Intervention

   Prevention. In 1995, NCI-supported researchers launched several studies focused on cervical cancer prevention, including an innovative study to address risk behaviors associated with an alarming increase of cervical neoplasias among young women. The researchers will develop, implement, and evaluate interventions that increase consistent condom use and reduce cigarette smoking, which is connected with increased cervical cancer risk. Smoking reduction is also the focus of another cervical cancer prevention study – the final goal is to reduce cervical cancer incidence and mortality. Researchers will design, implement, and evaluate an educational intervention for use at the time of a cervical cancer screening visit.

   Detection. Screening for cervical cancer should now be more effective with the introduction of an FDA approved quality control tool which will help labs identify pap smears which are suspicious and need to be re-examined by a cytotechnologist. The Autopap 300 QC, and similar systems such as PapNet, rescreen all pap smears that have been labeled as "normal" and selects those that need a second look. This will not necessarily reduce the number of false positives, but it will lower the number of abnormal smears which go undetected, hopefully leading to a greater number of precancerous and cancerous lesions being caught when they are easier to treat, or before becoming invasive.

   Treatment. Studies using SEER data are assessing the association between carcinoma in situ, treatment regimen, and subsequent pregnancy outcomes. The objective is to determine whether pregnancy outcome and method of delivery are influenced by a history of carcinoma in situ, diagnostic procedures, or treatment.

   ASCUS/LSIL Triage Study. NCI is launching a large national study to answer one of the most controversial questions in women's health: What should women and their doctors do about mild abnormalities that often show up on Pap tests? The results could affect the 2 to 3 million American women each year who learn that their Pap test has uncovered a mildly abnormal change in cells lining the cervix.

   Each year, Pap tests reveal serious, precancerous abnormalities called HSIL (high-grade squamous intraepithelial lesions) in about 300,000 women in the United States. There is little controversy about the management of HSIL; it must be treated to prevent cervical cancer. However, no consensus exists on the way to manage the far more common, milder abnormalities known as ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesions).

   The trial, known as ALTS (ASCUS/LSIL Triage Study), will test two major hypotheses. One is that follow-up with repeat Pap tests is a safe and effective way to manage ASCUS and LSIL. The second is that HPV testing can help in managing these mild abnormalities. The trial will also evaluate three different ways of managing ASCUS and LSIL: 1) colposcopy – a procedure in which a physician examines the cervix through a magnifying instrument and biopsies any abnormal areas; 2) repeating the Pap test every six months (because most abnormalities return to normal without treatment); and 3) testing for certain types of human papilloma virus (HPV), as a means to differentiate between abnormalities that need colposcopy and those best followed with repeat Pap tests at 6-month intervals.

4. Cancer Control

   In 1996, NCI's Office of Cancer Communications began developing a cervical cancer awareness program designed to promote the importance of Pap tests in detecting cervical cancer. The focus will be on reaching women ages 18-24 and 65 and older because they have the lowest screening rates. National activities will include distributing English and Spanish print and radio public service announcements. The program will also provide information for health professionals on how to access NCI resources and publications.

III. Ovarian Cancer

Approximately 26,800 U.S. women will be diagnosed with ovarian cancer and about 14,200 will die from it in 1997. The cancer death rate for ovarian cancer is declining and it is expected to be the fifth leading cause of cancer death in 1997, dropping from fourth place in 1995 and 1996. Though the death rate is declining, ovarian cancer still ranks second among gynecologic cancers in terms of incidence and causes more deaths than other reproductive cancers.

1. Biology

   Hereditary ovarian cancer susceptibility appears to be related to the BRCA1 and BRCA2 genes which also dictate a woman's chance of developing hereditary breast cancer. As mentioned in the breast cancer section of this report (pg. 4), only 10% of non-inherited ovarian and breast cancers are linked to alterations in the BRCA1 gene, as opposed to 45% of inherited breast cancer and 80% of families with ovarian and breast cancers. It is estimated that 39% of ovarian cancers in Ashkenazi Jewish women age 50 and under are linked to BRCA1. Furthermore, mutations in the p53 gene have been shown to be involved in ovarian cancer among others.

2. Risk

   Several factors have been connected to an increased risk of developing ovarian cancer including a family history of ovarian or breast cancer, increasing age, never having had children, and difficulty becoming pregnant. A reduction in risk is strongly linked to the number of pregnancies a woman has with an estimated 13% to 19% reduction of risk per pregnancy. Oral contraceptives also have a protective effect, reducing risk on average 5% to 10% for every year of use. Interestingly, factors that are often associated with breast cancer, such as age at first birth, age at menarche, age at menopause, and estrogen replacement therapy, appear to have little or no bearing on ovarian cancer risk.

3. Intervention

   Prevention. 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 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 who are selected at random to receive the screening tests being studied will have a physical exam of the ovaries, a blood test for the tumor marker known as CA125, and transvaginal ultrasound.

   Treatment. The PLCO results are not expected for a few years. In the meantime, new treatments have shown significant improvement in ovarian cancer outcomes, and the use of cisplatin for pregnant women with the disease is being studied.

   • Taxol™ – The recent success of paclitaxel (Taxol™) and cisplatin in treating advanced ovarian cancer in a Gynecologic Oncology Group (GOG) trial is expected to have a significant impact on the treatment for the disease. In this NCI sponsored phase III trial, the paclitaxel/cisplatin combination increased survival by 50% compared to standard therapy with cyclophosphamide and cisplatin.
   • Hycamtin™ – Commonly known as topotecan, is derived from the bark of a Chinese tree and was approved, in 1996, for use as a secondary therapy for women whose ovarian cancer had not responded to standard treatment. Phase III trials of topotecan, conducted in collaboration with NCI by SmithKline Beecham confirmed that 15% to 17% of the women who had not responded to standard therapy responded to topotecan, and 25% to 30% of women who had responded to standard therapy also responded to topotecan.
   • Cisplatin – Although ovarian cancer usually appears in older women, those of childbearing years can be susceptible to the disease. But, ovarian cancer has been discovered in pregnant women, in rare instances. In these cases, chemotherapy with single or multiple drugs, not including platinum drugs, has been reported to have essentially no harmful outcomes when the drugs were not given during the first trimester. However, NCI researchers found in animal studies that the platinum containing drug cisplatin crosses the placenta damaging placental DNA and the brains of fetuses that survived treatment. These observations imply that human fetuses may also sustain some DNA damage during maternal treatment for ovarian cancer.

IV. Uterine Cancer

Uterine cancer will be diagnosed in about 34,900 women in 1997 making it the fourth leading site of cancer incidence. However, only 6,000 deaths will be attributed to the cancer. The 5-year relative survival rate for uterine cancer when detected and treated early is 95% and when diagnosed regionally the survival rate is 66%.

Current risk factors are thought to include estrogen, early menarche, late menopause, never having children, and tamoxifen use. Adjuvant tamoxifen therapy has been commonly used to improve survival from postmenopausal breast cancer and to reduce the recurrence of breast cancer. To see if late effects of tamoxifen could adversely affect the risk-benefit ratio in ongoing chemoprevention trials, the risk of second cancers was evaluated among 87,323 women with breast cancer reported to NCI's Surveillance, Epidemiology, and End Results Program (SEER). The SEER studies reaffirm the slight risk of tamoxifen causing uterine cancer.

CANCERS WITH HIGH INCIDENCE OR MORTALITY FOR WOMEN

V. Colorectal Cancer

Cancer of the colon and rectum will account for approximately 64,800 new cases of cancer for women in 1997 (48,600 colon; 16,200 rectum), and about 27,900 deaths (24,000 colon; 3,900 rectum) making cancers of the colon and rectum combined the third leading cause of cancer death in women.

1. Biology

   It is estimated that 20% of colorectal cancers are hereditary, and in fact it is thought that up to 15% of colorectal cancers can be attributed to the Hereditary Nonpolyposis Cancer Syndrome (HNPCC). It has been shown that HNPCC is inherited as a mutation in one of four known DNA mismatch repair genes: MSH-1, MLH-1, PMS-2, and PMS-2, but about 65% of all mutations appear in MSH-1 and MLH-1. Current studies are focused on determining the prevalence of HNPCC and developing screening tests for carriers of the genetic mutations.

   To measure the true prevalence of HNPCC in the population, NCI researchers and other scientists recognized the need for standard criteria based on both pathology and genetics for identification of those with the syndrome. However, past criteria stressed only pathological or cellular means of identifying patients with the syndrome. The need to expand past standards to include the genetic component of the syndrome led to an NCI-supported workshop, in 1996, to develop a new set of criteria known as the Bethesda Criteria. The attendees now hope to publish the criteria and set-up databases and other resources to assist in HNPCC identification and research.

2. Risk

   Several studies have identified possible risk factors including high-fat, low-fiber diets, poor intake of fruit or vegetables, high intake of red meats, and low physical activity. Newer studies are showing that both estrogen and aspirin might reduce the risk of developing these cancers.

   Analysis of Nurses' Health Study data indicate that regular aspirin use, similar to doses recommended for the prevention of cardiovascular disease, substantially reduces the risk of colorectal cancer. This benefit becomes evident only after a decade of regular aspirin use; however, some research does indicate drawbacks to long-term use of aspirin, such as ulcers.

3. Intervention

   Prevention. NCI's Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial will address whether or not the use of flexible sigmoidoscopy, the currently used screening method for colorectal cancers, is effective in reducing colorectal cancer mortality.

   Treatment. The drug Camptosar™, commonly known as irinotecan, was approved by the FDA, in 1996, for the treatment of patients whose colorectal cancer has recurred or spread following standard treatment. NCI supported scientists extracted irinotecan's parent drug, camptothecin, from the bark of a Chinese tree in the 1960s. Years of research by NCI and pharmaceuticals have finally converted this natural product into an effective cancer drug.

VI. Lung Cancer

1. Biology

   Genetic Changes and Sputum Cytodiagnosis. Although, specific genetic changes take place in lung cells when they become precancerous, this was only observed in the precancerous tissue of patients who have already had lung cancer surgery. Thus, the University of Colorado SPORE in Lung Cancer launched a sputum cytology screening program targeted at patients with chronic pulmonary disease and smoking histories who had not been diagnosed with cancer. The researchers wanted to see if these specific genetic changes could be identified in any precancerous cells found in these patients, and if these changes could be used to diagnosis whether or not the patients had mild or severe precancerous lesions. Based on the previously observed genetic changes, scientists were able to diagnose 48% of people with a mild form of precancerous cells and 28% with a moderate or worse type of precancerous cells. Those with mild precancerous cells were more likely ex-smokers or lighter smokers than those with the more severe form.

   Lung Cancer Family Registry. The use of molecular genetic data in evaluating genetic risk of disease requires family-based data. The Johns Hopkins University Lung Cancer SPORE, University of Colorado, and University of Texas, Southwestern Medical Center, are jointly developing such a research resource. Accumulating evidence is indicating a role for genetic susceptibility factors, including familial aggregation of lung cancer, even after controlling for smoking.

   Plans include continued accrual of lung cancer families (beyond the 199 families to date). A national lung cancer family registry will be initiated by seeking lung cancer family clusters. This registry will serve as a valuable resource for future investigations.

   Chromosome 3. Deletions of the chromosome 3 short arm occur at a high frequency in all forms of lung cancer with rates in small-cell lung cancer (SCLC) near 100% and in non-small cell lung cancer (NSCLC) at about 75%. These observations suggest that the short arm of chromosome 3 encodes one or more genes whose loss is critical to lung tumor development and progression. Scientists supported by the University of Colorado SPORE believe they have found a site on the short arm which is undergoing loss in early lung cancer lesions.

   p53, RAR, raf, and MTS1. Many mutations, deletions, or amplifications of growth-promoting oncogenes and growth-inhibiting tumor suppressor genes have been found in lung cancer, including mutations of p53, the retinoic acid receptor-beta (RAR) gene, and the raf gene which is crucial in several signaling pathways. Mutations of the multiple tumor suppressor gene (MTS1) on the short arm of chromosome 9 may play a formative role in certain lung cancers. Studies are under way to determine if genetic alterations occur early or late in tumor progression and if they are connected to different clinical outcomes.

2. Risk

   Mutagen Sensitivity in African Americans. The results of a study regarding the use of mutagen sensitivity as a biological marker of lung cancer risk in African Americans supported the hypothesis of a higher prevalence of mutagen sensitivity (as an indicator of genetic susceptibility) in African-Americans diagnosed with lung cancer. Higher mutagen sensitivity was noted in former smokers than in current smokers, and was significantly associated with adenocarcinoma and squamous cell carcinoma. Data were collected in an ongoing study of inter-individual and ethnic differences in susceptibility to tobacco carcinogenesis

   Environmental Risks. Most lung cancers arise as a result of exposure to environmental or occupational cancer causing agents. NCI researchers have found that signature molecular lesions or molecular fingerprints reflect exposures to specific agents. For example, certain changes in p53 (a tumor suppressor gene) and ras (an oncogene) result from exposure to tobacco-related carcinogens, while other changes are linked to radiation exposure or other causes. In addition, Chinese researchers found that volatile chemicals released from rapeseed oil, widely used in cooking, can cause genetic mutations, a finding confirmed by NCI-supported researchers. Lung cancer risk is also increased by using indoor coal-burning heaters, and an Environmental Protection Agency supported study in south China strengthens the observation that heavy air pollution from burning fossil fuels can, independently of smoking, increase lung cancer risk.

   Hormonal Factors. One study has found a three-fold increase in incidence of lung cancer cases in women when compared to men with equal smoking histories. NCI supported scientists are exploring the role of hormonal stimulation in this apparent increased lung cancer susceptibility in women since lung tumors have receptors for estrogen and progesterone.

3. Intervention
   • Prevention: a) Beta-carotene; b) 13-cis retinoic acid; c) Watercress Consumption
   • Detection.
   • Treatment: a) Radiation vs. Radiation and Chemotherapy for NSCLC; b) New Treatment Modalities

OTHER TREATMENTS, DISEASES, AND INITIATIVES OF INTEREST

VII. Immunotherapy for Metastatic Cancers

There is no curative treatment for metastatic colon, lung and breast cancers. To develop a treatment for these types of cancers, NCI scientists isolated an antibody that reacts with the cells of these cancers and attached the antibody to a genetically modified form of a powerful bacterial toxin (Pseudomonas exotoxin A) to make a drug which specifically attaches to and kills these types of cancers. These new drugs are called immunotoxins.

For the past two years, a clinical trial with immunotoxin LMB-1 has been carried out at NCI. The results show that immunotoxins directed at colon, breast, and other epithelial malignancies could be used as future treatments. Clinical studies with an improved form of LMB-1, LMB-7, are already underway.

VIII. AIDS

AIDS is a major health concern for the American public. Incidence continues to increase among young women and men, particularly Hispanic and African-American. The only segment of the population that has experienced decreased incidence is older white males. As heterosexual transmission increases, so too does the rate of women overall who are contracting the disease, as well as the mother-to-infant transmission rates.

1. Biology

   Prevalence. Recent trends in the AIDS epidemic in the United States, documented by an NCI scientist, reveal that while the rate of new AIDS cases reported among those born before 1960 is approaching a plateau, the incidence rate among younger Americans continues to escalate. HIV incidence appears to increase rapidly, beginning in the late teens, with peak rates in the twenties. This unfavorable trend was seen mostly among younger white, black, and Hispanic men and women. In fact, between 1987 and 1992 there was a greater relative increase of HIV incidence for women compared to men. The only part of the U.S. population to experience a decline in incidence was older white males.

   The study used a statistical method called "back calculation" to examine the number of AIDS cases reported to the Centers for Disease Control and Prevention (CDC) and calculate the number of HIV infections each year required to produce the AIDS cases. Overall, the study highlights the need to intensify targeted prevention efforts among adolescents and young adults in each racial and ethnic group, along with special prevention efforts over a broader range of ages among minority men and women.

   CKR5. Researchers in several centers, including NCI, have found that the behavior of a gene known as CKR5 is of critical importance to a patient's progression from HIV infection to full-blown AIDS – or even to an individual's risk of becoming infected with HIV. 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% of Caucasians have inherited one mutated version of the CKR5 gene that destroys its function and one normal copy of CKR5. Although these individuals are susceptible to infection with the AIDS virus, they progress to AIDS more slowly than those with two normal CKR5 genes. 1.2% of Caucasians inherit two mutated copies of CKR5. These individuals are, for all practical purposes, genetically resistant to HIV infection, even when heavily exposed. These mutations are not observed outside the Caucasian population. The CKR5 mutation discovery emphasizes an important role for human gene variation in the AIDS epidemic and offers several potential avenues for therapy.

2. Risk – Mother-to-Infant Transmission

   Mother-to-Infant transmission of human immunodeficiency virus (HIV) results in pediatric AIDS and contributes significantly to infant mortality, especially in Africa. Studies of twins who were born to HIV-infected women indicated that most HIV transmission occurs during labor or delivery and pointed to the birth canal as the likely route of most transmissions. NCI's Viral Epidemiology Branch conducted a clinical trial to determine whether mother-to-infant transmission of HIV could be reduced by cleansing the birth canal with a solution containing a disinfectant called chlorhexidine. In collaboration with the Johns Hopkins University and the Queen Elizabeth Central Hospital in Blantyre, Malawi, in southern Africa, where 30% of the childbearing women are infected with HIV, 6,964 women who were in labor were enrolled in the trial. Half of the women had the birth canal cleansing before their infants were delivered, but this procedure did not reduce HIV transmission. Specifically, 27% of the cleansed women and 28% of the comparison women who had standard care had infants who were infected with HIV. This result suggests that other methods will be needed to reduce mother-to-infant transmission of HIV and also shows that the birth canal may not be the major route of viral transmission.

   It has been shown that mother-to-infant rate of HIV transmission can be reduced from 26% to 7% by administering AZT to pregnant HIV-infected women. This method offers hope to HIV-positive women of childbearing age. A recent NCI study confirmed this finding in rodent studies; however, the HIV-free offspring of female rodents given high-doses of AZT were found to have a higher incidence of cancers when they reached early adulthood. This study raised important issues which NCI, the National Institute on Allergy and Infectious Diseases, and a panel of independent scientists dealt with at a NIH conference held in January 1997. The panel continues to support the use of AZT to reduce the risk of mother-to-infant HIV transmission because the benefit of avoiding HIV infection outweighs other risks, furthermore the rodents studied received quantities of AZT that were proportionately several times larger than what would be received by a pregnant woman.

   To support the few studies of AZT transplacental transmission, NCI researchers are developing and validating methods to measure and pinpoint how AZT is incorporated into the DNA of cells grown in the lab and animal models. These studies' results may eventually be applied to human tissue samples and may lead to information on the dose-related DNA damage that may occur in fetuses whose HIV-positive mothers are treated with AZT during pregnancy.

IX. Minority Cancer Rate Differentials

Cancer disproportionately affects minority populations, low-income groups, and persons age 65 and over. Minority-specific differences are found in breast cancer, prostate cancer, cervical cancers, colorectal cancer, head and neck, and other cancers. NCI supports research to determine the basis for differing incidence and mortality rates and the means to reduce and control cancer in these populations.

Efforts are focused on learning why different cancer rates exist in certain segments of the population and on making benefits from new knowledge about cancer prevention, detection, diagnosis and treatment available to all.

A high priority is to improve NCI's capability to measure cancer rates and risks for diverse population segments. The Surveillance, Epidemiology, and End Results (SEER) Program is pursuing methods to increase coverage of Hispanics, Native Americans (including American Indians, Alaska Natives, Hawaiian natives, and American Samoans), migrants, and rural populations.

NCI is supporting etiologic and epidemiologic studies of the links between cancer, diet and a variety of environmental factors in minority or age-specific populations.

Under an initiative targeting Native American women, NCI is funding grants to test interventions that: address barriers to culturally appropriate cancer control services such as screening, diagnosis, treatment and rehabilitation; reduce cancer risk behaviors (high dietary fat intake, alcohol consumption); and provide technical assistance to help Native American women develop research skills and pursue careers in research.

X. Clinical Trials Recruitment Strategies for Females and Minorities

Strategies are being tested to address the problems of recruiting under-represented groups – ethnic minorities and females – to participate in clinical trials. Eleven regional conference grants have been awarded for conferences that will take place by October 1997. In addition, eight grant awards for specific projects examining recruitment strategies for female participation in clinical trials were also awarded this year.

RELEVANT RFAs, RFPs, PAs FY 1995

 

Occupational Exposure and Cancer Prevention/Control Research (CA-95-002) DCEG & DCPC The purpose is to promote cancer control research activities which focus on innovative epidemiologic studies among populations occupationally exposed to potential carcinogenic substances. Special emphasis is placed on investigating minority populations and women who have not been studied adequately in the past.

 

Cooperative Family Registry for Epidemiologic Studies of Breast Cancer (CA-95-003) DCEG The purpose of the proposed award is to stimulate a cooperative effort to: collect information from families with a history of breast cancer in order to serve as a resource for interdisciplinary studies on the causes of breast cancer, and to encourage translational research in this area; and to identify a population at high risk for breast cancer that could benefit from new preventive and therapeutic strategies.

 

Breast Cancer Surveillance Research (CA-95-004) DCPC The purpose is to expand current surveillance projects in areas that have not been adequately covered, specifically among urban African-Americans and rural areas. The research should focus on the operational aspects of breast cancer screening practices in the U.S. and should assess the effectiveness, efficiency, and cost of screening programs as they relate to the reduction of breast cancer mortality.

 

Specialized Programs of Research Excellence in Lung Cancer (CA-95-008) DCTDC This initiative is to expand the current Lung Cancer SPORE program by the addition of at least one new SPORE (making the total number three). Each SPORE will assemble a number of laboratory and clinical scientists to work together on lung cancer and to focus on moving innovative findings from the lab into research settings involving patients and populations.

 

AIDS-Associated Malignancies Clinical Trials Consortium (CA-95-009) DCTDC The purpose is to stimulate cooperative efforts to design and develop clinical trials with novel agents or using innovative approaches in patients with AIDS-associated cancers. NCI is also seeking talented scientists from research organizations to work with other members of the consortium and NCI's Cancer Therapy Evaluation Program to conceive, create, and evaluate new approaches to therapy of AIDS-related cancers.

 

Human Metabolic Studies of Modification of Dietary Fatty Acid Intake for Prevention of Breast, Prostate, and Colon Cancer (CA-95-010) DCPC The purpose is to stimulate investigator-initiated research to discover how modification in amount or type of fatty acid eaten may reduce risk for breast, prostate, or colon cancers. The goal is to clarify understanding of the relationship between dietary fatty acids and cancer in risk reduction.

 

Cooperative Group for Breast and Colo-rectal Cancer Clinical Trials (CA-95-011) DCTDC Applications were sought to establish a surgically oriented Clinical Trials Cooperative Group that will perform multi-institutional clinical trials in adult patients with breast and colorectal cancer. The Cooperative Group will be expected to conduct a broad spectrum of innovative therapeutic clinical trials that will advance the care of these patients.

 

Multi-institutional Cooperative Group for Clinical Evaluation of Magnetic Resonance Imaging in Breast Cancer (CA-95-014) DCTDC The intent is to establish a consortium of institutions who will, under a cooperative agreement, study the role of magnetic resonance imaging in improved detection and staging of breast cancer. NCI is also seeking talented scientists who will work with other members of the consortium to evaluate and optimize new approaches to breast cancer diagnosis.

 

National Action Plan on Breast Cancer Innovative Small Grant Program (CA-95-016) NCI This innovative small grant program is designed to promote research or outreach projects related to the following six priority areas: information dissemination, national biological resource bank, consumer involvement, breast cancer etiology, clinical trials accessibility, and breast cancer susceptibility gene issues.

 

Models for AIDS and AIDS-related Malignancies (PA-95-021) NCI & NIAID The purpose of this program announcement is to encourage investigators to develop useful and predictive biochemical, cellular, and in vivo models that can be used for the preclinical evaluation of new therapies against AIDS and AIDS-related malignancies.

RELEVANT RFAs, RFPs, PAs FY 1996

 

Women and Minority Recruitment: Small Grant Program (CA-96-003) DCPC The purpose of this small grant program is to launch pilot studies, test new ideas, or gather information that will lead to the development of effective models and strategies to improve the participation of women and minorities in cancer prevention and screening phase III research.

 

Women and Minority Recruitment: Intervention Testing (CA-96-004) DCPCThe intent is to fund research to develop, implement, and test well-defined, hypothesis-based interventions to improve the participation of women and minorities in cancer prevention and screening trials, particularly phase III research.

 

Program Projects in Nutrition and Basic Biology Research for Cancer Prevention (CA-96-005) DCPC This initiative will support multidisciplinary nutrition and basic biology research that seeks to improve understanding of the roles of dietary patterns, individual dietary constituents, and nutritional status in the development and prevention of cancer. Special emphasis will be placed on breast cancer, prostate cancer and cancer in women and minorities.

 

Studies of the Viral Etiology of AIDS-associated Malignancies (CA-96-008) DCB These grants will support investigators who wish to study the role of viruses and other biological agents in the cause and biology of malignancies associated with AIDS, such as Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphomas and HPV-associated cancers in HIV-positive and HIV-negative women.

 

Cooperative Family Registry for Epidemiologic Studies of Colon Cancer (CA-96-011) DCPC & DCEG Cooperative agreement applications are sought from investigators who wish to participate in an NCI supported network of organizations to create a Cooperative Family Registry for Epidemiologic Studies of Colon Cancer. The group will collect information from families with a history of colon cancer to provide resources for further study of the causes of colon cancer and research that translates laboratory discoveries into clinical treatments. The registry will also identify populations at high risk for colon cancer that could benefit from new preventive and treatment strategies.

 

Multi-institutional Cooperative Agreements for Clinical Evaluation of Magnetic Resonance Imaging in Breast Cancer (CA-96-012) DCTDC This initiative is seeking scientists from academic, non-profit and for-profit research organizations who will interact with other members of a cooperative consortium and NCI's Radiation Research Program to study the role of magnetic resonance imaging in improved breast cancer detection and staging, and to evaluate and optimize new approaches to breast cancer diagnosis.

 

Regional Conferences on Recruitment and Retention of Minority Participants in Clinical Cancer Research (CA-96-015) NCI The purpose is to provide support for regional conferences to share current information and strategies that will help clinical investigators in recruiting and retaining women and minority participants in clinical cancer research and to promote local/regional adaptations of these strategies.

 

Epidemiology of Lung Cancer: Interdisciplinary Studies (PA-96-008) DCEG This program announcement is designed to support grant applications for innovative interdisciplinary studies to better understand the causes and how to prevent adenocarcinoma and small cell cancer of the lung.

 

Aging Women and Breast Cancer (PA-96-034) The purpose of this broad-based program announcement is to expand the knowledge base on breast cancer in older women through studies in the fields of biology, clinical medicine, epidemiology, and the behavioral and social sciences and to inform the scientific community of the interests of NCI, the National Institute on Aging, the National Institute for Nursing Research, and the National Institute of Mental Health.

MEETINGS OF INTEREST HELD IN FY 1995 AND FY 1996

AIDS

 

Title: MULTICENTER HEMOPHILIA COHORT STUDY: 1995
ANNUAL MEETING SUMMARY
Description: Outlined activities of the Multicenter Hemophilia Cohort Study, with updates on the study's findings regarding hepatitis viruses and liver disease, AIDS and related issues, and targeted issues involving social and economic matters, new products, and AIDS-related cancers.
Date: 9/21-22/95
Location: Washington, D.C.
Organization/Sponsors: NCI/DCEG

Breast

 

Title: INTERGROUP BREAST CANCER CORRELATIVE
SCIENCE SUBCOMMITTEE
Description: Organizational meeting to determine interest in collaboration among the cooperative groups in future correlative breast cancer studies.
Date: 5/22/95
Location: Los Angeles, CA
Organization/Sponsors: NCI

 

Title: HIGH DOSE CHEMOTHERAPY WITH STEM CELL SUPPORT
FOR THE TREATMENT OF BREAST CANCER
Description: This meeting focused on ways to increase accrual to bone marrow transplant trials for women with breast cancer.
Date: 3/30/95
Location: Bethesda, MD
Organization/Sponsors: NCI/DCTDC/CTEP

 

Title: HORMONES, HORMONE METABOLISM, AND BREAST CANCER
Description: Participants assessed the state-of-the-art science in measurement and metabolism of hormones, the effects of hormones in the development of breast cancer, and major research gaps and data needs.
Date: 9/95
Location: Tulane University, New Orleans, LA
Organization/Sponsors: NCI/NAPBC/Tulane University

 

Title: LOCALIZATION OF THE BRCA1 GENE PRODUCT
Description: Various extramural research groups were gathered by NCI's director to meet and discuss the controversy over the localization of the BRCA1 gene product.
Date: 5/13/96
Location: Bethesda, MD
Organization/Sponsors: NCI

Estrogens

 

Title: ESTROGENS AS ENDOGENOUS PROCARCINOGENS: A MOLECULAR ORIGIN OF MUTATION AND CANCER?
Description: A half-day symposium on the role of estrogens in carcinogenesis followed by the first biannual meeting of the Complimentary, Collaborative Coalition, a group of scientists from many disciplines who have formed an alliance to focus on the role of estrogens in carcinogenesis.
Date: 5/29-30/96
Location: Bethesda, MD
Organization/Sponsors: NCI/DCB/Chemical and Physical Carcinogenesis Branch

Gastrointestinal

 

Title: GENETIC SCREENING FOR COLORECTAL CANCER
Description: Recent breakthroughs in the field of genetic screening for colorectal cancer, as well as their implications were discussed.
Date: 5/10-11/95
Organization/Sponsors: NCI/DCPC/Early Detection Branch

 

Title: THE INTERSECTION OF PATHOLOGY AND GENETICS
IN HNPCC SYNDROME
Description: The meetings focus was the merging of pathology and genetics to develop new, genetically-based guidelines, known as the Bethesda Criteria, for the diagnosis of the Hereditary Nonpolyposis Colon Cancer Syndrome.
Date: 11/11-12/96
Location: Rockville, MD
Organization/Sponsors: NCI/American Joint Commission on Cancer/International Collaborative Group on HNPCC

Gynecologic

 

Title: GYNECOLOGIC ONCOLOGY GROUP (GOG)
TRANSLATIONAL RESEARCH RETREAT
Description: This meeting's focus was to find new opportunities in clinical research and to work basic sciences into the design of clinical protocols.
Date: 4/21-23/95
Location: Chantilly, VA
Organization/Sponsors: NCI/DCB/Organ Systems Coordinating Branch