Full Text CA-92-20 EPIDEMIOLOGY OF OVARIAN CANCER NIH GUIDE, Volume 21, Number 27, July 31, 1992 RFA: CA-92-20 P.T. 34 Keywords: Epidemiology Cancer/Carcinogenesis Etiology National Cancer Institute Letter of Intent Receipt Date: October 15, 1992 Application Receipt Date: November 12, 1992 PURPOSE The Division of Cancer Etiology of the National Cancer Institute (NCI) invites grant applications for innovative interdisciplinary epidemiologic studies to better understand the etiology of ovarian cancer and the means of prevention. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Epidemiology of Ovarian Cancer, is related to the priority area of cancer. Potential applicants may obtain a copy of a "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (Telephone 202/783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign non-profit and for-profit institutions, public and private, such as colleges, universities, hospital, research laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from or involving minority institutions, individuals, and women are encouraged. MECHANISM OF SUPPORT This RFA will be supported through the NIH traditional research project grants (R01) and the Interactive research project grants (IRPG) (R01). Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA is a one-time solicitation. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed five years. Competitive continuation applications will compete with all other unsolicited applications and be reviewed by standing Division of Research Grants study sections. If the NCI determine that there is a sufficient continuing program need, the NCI may announce a request for renewal applications. FUNDS AVAILABLE The estimated funds (total costs) available for the first year of support for this initiative is $2.0 million. The expected number of awards is five to eight. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plan of the NCI, the award of grants pursuant to this RFA is contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Ovarian cancer is the most lethal gynecologic malignancy. On a worldwide basis, it is estimated that over 140,000 cases are diagnosed annually, representing more than 4 percent of all cancer cases in women. In the United States, incidence and mortality estimates for 1990 indicated that approximately 20,500 new cases were diagnosed and 12,000 women died. Overall, the probability that a woman will be diagnosed with ovarian cancer in her lifetime is 1 in 70. The incidence rate is currently 46 percent higher in whites than in blacks. The incidence of ovarian cancer seems to have decreased slightly since 1973, but the survival rate has changed very little. Survival is related to age. During the period 1981-86, women diagnosed prior to age 65 had a 5-year relative survival rate of 48 percent compared to 24 percent for those diagnosed at age 65 and older. The highest ovarian cancer rates are reported from industrialized countries, with the exception of Japan. The age-adjusted mortality rates are 1.69, 3.02, 7.04, and 11.02 per 100,000 for Japan, Italy, the United States, and Denmark, respectively. Japanese migrants to Hawaii and their first-generation offspring have a higher incidence of ovarian cancer than women in Japan, suggesting environmental influences. The trends in ovarian cancer over the last two decades indicate increasing rates in low-risk areas such as Japan and Singapore. A few aspects of ovarian cancer epidemiology are well documented, such as an inverse association with parity and oral contraceptive use. A role for other menstrual, reproductive, and hormonal factors and diet has been suggested, but remains to be confirmed. Cancers of the breast and ovary appear to share some etiologic factors. For example, women with breast cancer have twice the expected risk of ovarian cancer, and women with ovarian cancer have a three-to-fourfold increase in the risk of subsequent breast cancer. Epithelial carcinomas account for 80-90 percent of ovarian neoplasms. The remaining ovarian tumors originate from the germ or stromal cells. Epithelial tumors are classified as benign, malignant (invasive), and tumors of low malignant potential (or borderline malignancy). The peak incidence of benign epithelial tumors occurs in the 20-40-year-old group, whereas the peak incidence for malignant neoplasms, occurs in the 40-70-year-old group. The peak incidence of tumors of low malignant potential is between ages 30 and 40. The 5- and 10-year survival rates for patients with low malignant potential tumors are 98 percent and 74 percent, respectively, compared with 34 percent and 29 percent for patients with invasive epithelial tumors. Although the ovary is not the primary target tissue for estrogens, estrogen receptors (ER) and progesterone receptors (PGR) have been found in both benign and malignant ovarian tumors. The ER and PGR content in ovarian carcinomas has not yet been correlated with the histologic type and grade of the tumor, or with risk factors. It has been proposed that repeated minor trauma to the epithelial surface of the ovary, caused by incessant ovulation, allows promotion of cells bearing allele loss and, by inference, those carrying inactivated tumor-suppressor genes. This may lead to uncontrolled cell division and malignant transformation. A molecular basis for this hypothesis comes from the studies of variable number tandem repeat (VNTR) probes used to analyze DNA from ovarian tumors. Allele loss was observed on the long arm of chromosome 17 in more than 80 percent of malignant ovarian tumors. Such allele losses have been shown to represent loss of tumor-suppressor genes. It is conceivable that another as yet unidentified gene(s) may play an essential role. Ovarian cancer families provide an excellent opportunity for epidemiologic studies. Risk estimates based upon familial ovarian cancer aggregations suggest a three-to-fourfold excess risk for ovarian cancer among first degree relatives of ovarian cancer patients when compared to the risk in the general population. Linkage studies are needed to determine if altered germ line alleles contribute to the familial predisposition of ovarian cancer. Formation of an international computerized registry of afflicted families with an associated family member DNA bank could be a valuable asset in having the actual genes cloned. The correlation of ovarian and breast cancers in some families suggests that genetic variation in steroid hormone metabolism may be an important factor in the susceptibility to ovarian cancer. Recently, a collaborative analysis of 12 U.S. case-control studies of ovarian cancer was carried out to assess the influence of events affecting ovulation, such as timing of menarche and menopause, timing and outcome of pregnancies, duration of breast feeding, duration of oral contraceptive use, exogenous estrogen use and prior pelvic surgeries. There were clear trends of decreasing ovarian cancer risk with increasing parity, duration of breast feeding and oral contraceptive use, and increasing number of pregnancies regardless of outcome. There was a weak trend relating risk to age at menarche, no clear trend relating risk to age at menopause, and greater risk reduction per month of pregnancy than per month of oral contraceptive use. Among nulliparous women, risk did not vary by marital status or gravidity. There was a weak association with duration of longest pregnancy attempt, total duration of unprotected intercourse, and history of clinically diagnosed infertility. The risk was elevated among women who had used fertility drugs. A history of tubal ligation or of hysterectomy with ovarian conservation was associated with reduced risk. Oral contraceptives were generally less protective against tumors of low malignant potential. Also, the percent risk reduction associated with a month of pregnancy was greater for younger women than for older women. The percent risk reduction attributed to a year of oral contraceptive use was greater among older women, suggesting that older, higher potency oral contraceptive drugs may be more protective than recent formulations. The findings of a meta-analysis of 3 hospital-based case-control studies of ovarian cancer conducted in Europe were similar to those in U.S. studies. An interesting observation in this analysis was that the protective effect of full-term pregnancy depended upon the age at which it occurred. Women who bore their first child at age 35 or older were at slightly increased risk than those who bore their first child at age 24 or earlier. Correlation studies and international differences have suggested an association of diet with ovarian cancer. Positive correlations with higher intake of fats, proteins and calories and negative correlations with frequent consumption of green vegetables, carrots and greater vitamin A intake have been reported. With regard to alcohol consumption, the findings have been inconsistent. Lactose consumption has been suggested as a risk factor for ovarian cancer, with low galactose transferase activity as a genetic marker for increased susceptibility. Other The purpose of this initiative is to stimulate innovative epidemiologic research into the origins of ovarian cancer. Collaborations of several disciplines and research institutions are particularly encouraged. Whenever possible, research designs should make use of existing resources, such as familial ovarian cancer registries and specimen repositories. Projects will be evaluated on the basis of the potential for enhancing the understanding of ovarian cancer etiology and means of prevention. The initiative permits a range of epidemiologic and interdisciplinary investigations of ovarian cancer including, but not limited to: o Epidemiologic studies of - the long-term effect of combination oral contraceptives, with special reference to age at initial use and age at cessation of use, on ovarian cancer risk by pathologic type; - the relationship between hormone replacement therapy and ovarian cancer risk; - the use of fertility-promoting drugs, ovarian stimulants, or in vitro fertilization in relation to ovarian cancer risk; - the interrelationship of tubal ligation, hysterectomy, hormone levels, and ovarian cancer risk; - the association of unilateral oophorectomy, age at oophorectomy, and ovarian cancer risk; - the influence of diet and physical activity and their interaction on ovarian cancer risk; - the relationship of exposure to potential oocyte toxins such as talc, galactose, caffeine, smoking, and other agents to ovarian cancer risk among women who use and those who do not use oral contraceptives. o Molecular epidemiology studies exploring differences in genetic predisposition to ovarian cancer due to variations in susceptibility genes, hormone metabolism, DNA repair activities, chromosome sensitivity to mutagens or other factors. o Molecular epidemiologic studies using existing registries of ovarian cancer families. o Analytic studies of ovarian cancer to determine the impact of changes in exposure due to migration from low- to high-risk regions and/or to secular changes in lifestyle and environment. o Studies of racial/ethnic differences in the histologic and cytologic parameters of ovarian cancer that may reflect differences in exposure or susceptibility. o Population-based studies of the correlation of estrogen and progesterone receptor content of ovarian tumors with histologic type, grade, clinical prognosis, and exposure history. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF FEMALES AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and females in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and females in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If females or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in the Research Plan, 1-4, AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from females and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of females applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of females or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are requested to submit, by October 15, 1992, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the names of other key personnel and participating institutions, and the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NCI staff to estimate the potential review workload and to avoid conflict of interest in review. The letter of intent is to be sent to: Dr. A.R. Patel Extramural Programs Branch Epidemiology and Biostatistics Program Division of Cancer Etiology National Cancer Institute 6130 Executive Boulevard Executive Plaza North, Suite 535 Rockville, MD 20892 Telephone: (301) 496-9600 APPLICATION PROCEDURES Applications are to be submitted on for PHS 398 (rev. 9/91) that is available at most institutional business offices, and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892, telephone 301/496-7441. The format and instructions applicable to research grant applications must be followed. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator must be included with the application. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may be not reach the review committee in time for review. In addition, the number and title of the RFA must be typed on line 2a of the face page of the application and YES must be checked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package to the Division of Research Grants at the address below. The photocopies must be clear and single sided. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, send two additional copies of the application to: Referral Officer Division of Extramural Activities National Cancer Institute Westwood Building, Room 838 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by November 12, 1992. If an application is received after that date, it will be returned without review. If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. IRPG applications may be submitted from a single institution or may include arrangements with one or more other institutions if appropriate. Each application will be considered on its own merit as an individual research project. Therefore, applicants for IRPGs MAY NOT concurrently submit R01 applications that represent significant duplication of the efforts described in the applicant's IRPG. In this regard, it should be noted that the NCI will consider funding meritorious individual IRPG applications if it is not possible to fund the IRPG package as a whole. (Interactive Research Projects Grants for Cancer, PA-92-29, NIH Guide for Grants and Contracts, Vol. 21, No. 1, January 10, 1992). Concurrent submission of program project (P01) applications is prohibited. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the Division of Research Grants (DRG) for completeness. Incomplete applications will be returned to the applicant without further consideration. Preliminary evaluation for responsiveness to the RFA is an NCI program staff function. If an application is judged to be nonresponsive, the applicant will be contacted and given an opportunity to have it considered along with other unsolicited grant applications received by the NIH. Applications responsive to this solicitation will be reviewed by an appropriate review group convened by the Division of Extramural Activities, NCI. The initial review will be for scientific merit. The second level of review by the National Cancer Advisory Board considers the special needs of the NCI and the priorities of the National Cancer Program. Review criteria for RFAs are generally the same as those for unsolicited research grant applications: o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; o availability of resources necessary to perform the research. The review group will critically examine the submitted budget and will recommend an appropriate budget and period of support for each scored application. AWARD CRITERIA The earliest anticipated award date is July 1, 1993. In addition to technical merit, reasonableness of the budget in comparison with other applications, will be taken into consideration in making an award. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. A.R. Patel Extramural Programs Branch Epidemiology and Biostatistics Program Division of Cancer Etiology National Cancer Institute 6130 Executive Boulevard Executive Plaza North, Suite 535 Rockville, MD 20892 Telephone: (301) 496-9600 Direct inquiries regarding fiscal matters to: Ms. Jean M. Cahill Supervisory Grants Management Specialist National Cancer Institute 6120 Executive Boulevard Executive Plaza South, Suite 243 Rockville, MD 20892 Telephone: (301) 496-7800, ext. 47 AUTHORITY AND REGULATIONS This cancer cause and prevention research program is described in the Catalog of Federal Domestic Assistance No. 93.393. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health System Agency review. .
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