Ovarian Cancer Prevention Workshop
Division of Cancer Prevention (DCP)
National Cancer Institute
The Westin San Francisco Airport Hotel
March 31, 2000
DCP Executive Summary: Conclusions from the Workshop
In the United States, approximately 23,000 new cases of ovarian cancer will be diagnosed in the year 2000, and there will be about 14,000 deaths. Despite the precept that early detection may increase the opportunity for effective treatment, the identification of effective population-based screening methods for ovarian cancer has yet to be accomplished, and is not expected in the near future. Around two-thirds of ovarian cancer cases continue to be diagnosed at stage 2 or higher. After completion of aggressive surgery and chemotherapy for advanced disease, residual malignancy often remains, and usually recurs within 3 years of diagnosis. With the preponderance of cases diagnosed in later stages, the opportunity to understand the early biology of ovarian cancer is further limited. In view of the challenges inherent to the development of effective screening and treatment, consideration may also be gainfully directed at strategies involving risk identification coupled with clinical intervention early in the disease process to prevent morbidity and mortality by reducing ovarian cancer incidence. Incidence-reducing initiatives are in their infancy.
In recent years, the National Cancer Institute's (NCI) Division of Cancer Prevention (DCP) has periodically assessed the status of its research portfolio for ovarian cancer prevention. In 1995, and again in 1998, members of the Division met with representatives of the extramural research community and other NCI Divisions to review the state of science related to ovarian carcinogenesis, and to discuss the future directions that programmatic initiatives and funding might take. In consideration of recent advances in molecular biology, a workshop was sponsored by DCP in March 2000 to identify basic science opportunities for the development of interventions directed at molecular targets pivotal to ovarian carcinogenesis. The workshop discussion was informed by a series of ten brief scientific presentations and focused on risk specification, early natural history, and translational models of clinical intervention.
Ovarian Cancer Risk Specification:
A population with at least a 10-fold increase in ovarian cancer risk compared with the general population can be specified on the basis of a known critical mutation in BRCA1 or BRCA2, a family history consistent with membership in a family carrying mutated BRCA1 or BRCA2, or a family history consistent with membership in an HNPCC (hereditary non-polyposis colon cancer) family where ovarian cancer has been diagnosed. Known germline mutations are thought to account for about 9% of ovarian cancer cases: BRCA1, 4%; BRCA2, 3%; and HNPCC, 2%. Some of the risk in first degree relatives of ovarian cancer patients is attributable to germline mutations. It is not clear that preventive strategies that reduce ovarian cancer in germline mutation carriers will also be beneficial in the prevention of sporadic ovarian tumors. No multivariate statistical tool is available to compute absolute ovarian cancer risk estimates for the immediate future of a woman with specific known risk factors.
The clustering (2 or more) of abnormal ovarian epithelial histological features may be associated with the subsequent development of ovarian cancer. The ordering of molecular events in ovarian carcinogenesis is not clear. Abnormalities in HER-2/neu, p53, and NOEY2 are likely to be involved. Overexpression of PIK3CA and ZNF217 may be early events in ovarian carcinogenesis. Targets such as these suggest the possibility of interventions specifically designed to reverse the molecular pathology introduced by these events. For example, a PIK3CA inhibitor would be expected to increase apoptotic elimination of early aberrant cells. If this were the case, a drug with this function and acceptable toxicity might be a reasonable preventive approach. Basic research is needed to design drugs with the desired activity at the target of interest at acceptably low levels of toxicity. Another target-based preventive approach involves the development of a multivalent vaccine that generates a cytotoxic immune response to cellular abnormalities such as overexpression of HER2/neu. A vaccine has been demonstrated to generate a T-cell response against HER2/neu with immunologic parameters similar to known effective vaccines. The projected success of such an approach is based on the concept of a multivalent vaccine which requires the identification of a panel of susceptible antigens. Further research is needed to identify antigens in addition to HER2/neu that would be appropriate for targeting by a multivalent vaccine.
Observational Evidence for Potential Prevention Agents:
Epidemiologic studies suggest that oral contraceptives or their progestational component may be able to reduce ovarian cancer risk by as much as 50%. The effect is not well defined and the appropriate formulation for intervention is subject to question because of longitudinal change in contraceptive formulations. The protection of hormonal factors is further suggested by ovarian cancer risk reduction associated with parity and breast feeding. A randomized trial using 4-hydroxyphenyl retinamide (4-HPR) has suggested that this retinoid may offer some protection against the development of ovarian cancer. This evidence is provided by a small number of cases for a secondary endpoint in an adjuvant breast cancer treatment trial. In addition to oral contraceptives and retinoids, COX-2 inhibitors, SERMs and selenium have been mentioned as other candidate agents for ovarian cancer prevention.
Translational Models of Clinical Intervention:
Two small prevention-related studies are in progress and use a clinical model based on a cohort of women who plan to have prophylactic oophorectomy for ovarian cancer risk reduction. In these studies, 4-HPR and OC's are the test agents under investigation.
Summary Conclusions from Presentations and Discussion:
- Research should continue to identify risk factor models that allow more accurate prediction of individual ovarian cancer risk for counseling and for identification of high risk populations for clinical studies.
- Basic research should continue to identify targets that contribute to ovarian carcinogenesis, so that agents with specificity for those targets can be designed.
- Further research is needed to identify antigens in addition to HER2/neu that would be appropriate for targeting by a multivalent cancer prevention vaccine.
- Small studies in women planning to have prophylactic oophorectomy may be useful to generate biomarker data related to prevention questions and to obtain tissue that can be used to identify molecular targets that are critical to ovarian carcinogenesis.
- Insufficient information is available at this time to justify proceeding with a large, phase 3 ovarian cancer prevention trial.
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