About 27,000 new cases of ovarian cancer are diagnosed in the United States annually. In cases in which the cancer is confined to the ovaries surgical removal of the tumor usually is curative. Unfortunately, in most women with this disease the cancer is found to have spread extensively in the abdominal cavity at diagnosis. In these patients, surgery and chemotherapy treatments have increased the average survival to about 3 years, but few are cured. There are three potential approaches to decreasing ovarian cancer deaths: (1) more effective treatment of advanced stage cancers, (2) better screening tests that allow more cases to be detected while still confined to the ovaries, and (3) prevention of the disease. All of these avenues should be explored, but we believe that prevention represents the most feasible approach.

Although it is not widely appreciated, factors such as pregnancy, breastfeeding, and birth control pills, which reduce the number of times a woman ovulates during her life, strikingly decrease the incidence of ovarian cancer. Women who use the pill for more than 5 years or have 3 children decrease their risk of ovarian cancer by more than 50'. A strong association exists between ovulation and ovarian cancer, but the biological mechanisms responsible are poorly understood.

Our multidisciplinary ovarian cancer research group has been actively involved in studies that seek to elucidate the etiology of ovarian cancer and to translate this knowledge into effective preventive strategies. In this project, we hope to continue these efforts on several fronts. We will establish an Epidemiology and Tissue Core, directed by Dr. Schildkraut (Epidemiologist), which will collect samples of frozen ovarian cancer tissues and blood from 500 new ovarian cancer cases in North Carolina. In addition, 500 age- and race-matched control subjects from the Gynecology Clinics of the Duke University Health System will be enrolled and a blood sample obtained. Cases and controls will be interviewed on the telephone regarding known risk factors for ovarian cancer.

In a recent study, we found a strong association between high numbers of lifetime ovulatory cycles and alterations of the p53 tumor suppressor gene in ovarian cancers. In Project 1 of this proposal, directed by Dr. Berchuck (Gynecologic Oncologist), we will attempt to confirm this association. More broadly, we will determine whether specific ovarian cancer risk factors are associated with acquired molecular alterations. The goal of this project is to define more homogenous subsets of ovarian cancer based on molecular and epidemiologic characteristics. This could be critical as we strive to develop prevention strategies, as the optimal means of prevention may vary between different subsets of ovarian cancers.

In Project 2, directed by Dr. Futreal (Molecular Geneticist), we will examine the role of inherited genetic polymorphisms in the development of ovarian cancer. Although most of the genes responsible for hereditary ovarian cancer syndromes (e.g., BRCA1) likely have been discovered, there is evidence to suggest that subtle changes (polymorphisms) in other genes may also affect cancer susceptibility.

Dr. Futreal will investigate whether genetic polymorphisms affect ovarian cancer susceptibility. Since the effect of cancer susceptibility genes may be modified by other genes and/or exposure, he will determine whether gene-gene and gene-environment interactions affect ovarian cancer susceptibility. Because of the relatively low incidence of ovarian cancer, the ability to identify ¿high risk¿ subsets of women is critical if we hope to translate our emerging understanding of the etiology of ovarian cancer into effective prevention strategies. Recently, we have demonstrated that administration of the oral contraceptive progestin levonorgestrel to non-human primates stimulates elimination of epithelial cells from the surface of the ovary. This suggests that clearance of damaged cells from the ovary may account for part of the protective effect of pregnancy and birth control pills against ovarian cancer.

In Project 3, Dr. Rodriguez (Gynecologic Oncologist) will explore the mechanism and potential use of progestins as ovarian cancer chemopreventive agents. This will include studies that examine the effect of levonorgestrel on the ovaries of women (without ovarian cancer) who are undergoing oophorectomy. In addition, we will test the ability of levonorgestrel to inhibit the development of ovarian cancer in the domestic fowl, which is one of the few other species in which epithelial ovarian cancer occurs.

We believe that the studies outlined in this proposal will enable us to increase our understanding of the etiology of ovarian cancer, to define subsets of women who are at increased risk and to develop effective chemopreventive strategies designed to decrease ovarian cancer incidence, and mortality.