Hormonal and Reproductive Risk Factors for Epithelial Ovarian Cancer by Tumor Aggressiveness

Abstract

Background Approximately half of epithelial ovarian cancers are fatal within three years; however about 35% of women survive at least ten years. In the Nurses’ Health Study, New England Case-Control Study, Australian Ovarian Cancer Study, and NIH-AARP Diet and Health Study, we investigated potential differences in the associations with ovarian cancer risk factors by tumor aggressiveness, defined based on time from diagnosis until death. Methods We calculated relative risks (RR) and 95% confidence intervals (CI) for associations of known or suspected ovarian cancer risk factors with rapidly fatal (death within three years of diagnosis) and less aggressive tumors (all others) using Cox proportional hazards competing risks analysis (NHS, AARP) or polytomous logistic regression (NECC, AOCS). Results were combined using random effects meta-analysis. Results Increasing age was associated with greater risk of rapidly fatal versus less aggressive disease (OR, 5-yr increase: 1.39; 95% CI: 1.29–1.49 vs. OR: 1.09; 95% CI: 1.03–1.16, respectively; p-diff<0.0001). OC use was associated with a greater decreased risk of rapidly fatal (OR, 5-yr increase: 0.69; 95% CI: 0.58–0.82) versus less aggressive disease (OR: 0.81; 95% CI: 0.74–0.89; p-diff=0.002). Conversely, increasing parity was associated only with less aggressive disease (OR, per child: 0.87; 95% CI: 0.81–0.93). Conclusion In this analysis of 4,342 cases, there were clear differences in risk factors for rapidly fatal vs. less aggressive ovarian tumors. Impact Differences in risk factor associations by tumor aggressiveness suggests the developmental pathways through which the tumors develop and may be important for developing primary prevention strategies for the most aggressive cancers. Go to: Introduction Ovarian cancer is the fifth most common cause of cancer death among women (1). In SEER data (1988–2007), 47.1% of patients died within three years of diagnosis, but ten year survival was 34.1% (2). The wide variability in ovarian cancer survival may be due, partly, to its heterogeneity, which can be characterized by differences in histology and molecular alterations (3). Recent data suggest that high grade serous carcinomas originate in the fallopian tube rather than the ovarian surface epithelium (OSE) (3). Based on these data, ovarian tumors have been classified into three developmental pathways (3). Type 1/2 tumors include low-grade serous, mucinous, endometrioid, and clear cell carcinomas that arise from the OSE or from endometriotic implants, and are characterized by mutations in KRAS, BRAF, PTEN, or PIK3CA. Type 3 tumors are high-grade serous and endometrioid tumors with mutations in TP53; these tumors arise in the fallopian tube and have the worst prognosis (3, 4). Ovarian cancer risk factors associations may differ by developmental pathway. However, it is not feasible to determine developmental pathway in large-scale epidemiologic studies, primarily because determining cell of origin requires extensive sectioning of the tubes and ovaries and tumor molecular profiling only recently has become cost-effective. However, the most aggressive tumors (i.e., type 3) are likely to be quickly fatal, whereas women with less aggressive tumors (i.e., types 1/2) will have longer survival. Identifying differences in risk factor associations between the most rapidly fatal vs. less aggressive cancers could improve our understanding of ovarian carcinogenesis and better target prevention. Therefore, we conducted an analysis comparing risk factor associations between women who died within three years of diagnosis to women who survived at least three years post-diagnosis in four studies.