Chemoprevention of Ovarian Cancer: Modulation of Biomarkers in Women at Low- and High-Risk for Ovarian Cancer Using Fenretinide (4-HPR) and Oral Contraceptives

Principal Investigator: David M. Gershenson, M.D.

Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and a synthetic form of vitamin A called N-(4-hydroxyphenyl) retinamide (4-HPR) may reduce the risk of ovarian cancer, but mechanisms of action of these agents remain unknown.

Several studies have correlated the risk of ovarian cancer with frequency of ovulation. OCPs suppress ovulation, but the decrease in risk of developing ovarian cancer is not directly proportional to the number of menstrual cycles suppressed. This suggests that other mechanisms might also contribute to chemopreventive effects.

A recent study in primates indicates that treatment with oral contraceptives or with progestins can increase apoptosis (cell death) in ovarian surface epithelial cells. Apoptosis is considered a defense mechanism of the organism against cancerous cells. Our group has found that transforming growth factor-beta (TGFß) induces apoptosis in abnormal ovarian cells.

Consequently, TGFß may provide a surveillance mechanism for eliminating emerging malignant cells in cooperation with 4-HPR and OCP. The purpose of this project is to test the potential activity of OCP and 4-HPR for the prevention of ovarian cancer among women at low- and high-risk for ovarian cancer.

We will explore the underlying mechanisms of the preventive activity of these compounds and we will identify potential molecular markers that can be used as markers of their efficacy to prevent cancer to be used in the design of future studies. Women at low-risk for ovarian cancer will be selected among women undergoing elective bilateral salpingo-oophorectomy (BSO) for benign conditions (Low-risk women trial). Women at high-risk for ovarian cancer (based on family history) will be selected among women undergoing elective BSO for prophylaxis of ovarian cancer (High-risk women trial). Eighty-one low-risk and 81 high-risk women will be recruited and assigned to receive OCP, 4-HPR or placebo for six weeks before undergoing BSO. A high-risk woman will be defined as a woman with 10% or higher probability of having a BRCAI/BRCA2 mutation based on family history. Low-risk women will be identifed at Lyndon B. Johnson and Hermann Hospitals in Houston, Texas. High-risk women will be identified at The University of Texas MD Anderson Cancer Center and Baylor College of Medicine in Houston, Texas, the Southwestern Medical School in Dallas, Texas, and the Northwestern Medical Center in Chicago, Illinois. Women assigned to 4-HPR will receive 200 mg per day for six weeks with a three-day drug holiday, and women assigned to the OCP arm will receive Ortho-Novum 1/35. This study will provide information on the mechanism of action of these drugs and their potential use in future studies.

Key Words: Chemoprevention, biomarkers, oral contraceptives, 4-BPR, fluorescence spectroscopy