Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium

abstract
June 20, 2016 
 Division of Cancer Epidemiology and Genetics, National Cancer Institute

Purpose An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). 

Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. 

Results Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78) and clear cell (RR, 0.68) carcinomas. Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors. Family history of breast cancer had modest heterogeneity. Smoking was associated with an increased risk of mucinous (1.26) but a decreased risk of clear cell (RR, 0.72) tumors. Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. 

Conclusion The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

Footnotes

• Supported by Department of Defense Ovarian Cancer Research Program Grant No. W81XWH-12-1-0561. The UK Breakthrough Generations Study is supported by Breakthrough Breast Cancer and the Institute of Cancer Research. The Institute for Cancer Research is supported by National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Also supported by K05 CA154337 from the National Cancer Institute (NCI) and Office of Dietary Supplements (VITAL [Vitamins and Lifestyle study cohort]); R01 CA39742 (Iowa Women’s Health Study); National Institutes of Health/NCI grant UM1 CA182876 (Singapore Chinese Health Study); CA047988, HL043851, HL080467, and HL099355 (Women’s Health Study); CA164973 (Multiethnic Cohort); R01 CA77398 and UM1 CA169417 (California Teachers Study); UM1 CA186107, P01 CA87969, UM1 CA176726, and R01 CA67262 (Nurses’ Health Study, Nurses’ Health Study II); grants from the Swedish Cancer Society and Swedish Research Council (Swedish Women’s Lifestyle and Health cohort study); and the Swedish Research Council (Swedish Mammography Cohort). All aspects of the Cancer Prevention Study II were funded by the Intramural Research Program of the American Cancer Society and by the NCI Intramural Research Program, Intramural Research Program of the National Institutes of Health, and National Institute of Environmental Health Sciences (Z01ES044005; Sister Study). The coordination of European Prospective Investigation Into Cancer (EPIC) is supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (France); German Cancer Aid, German Cancer Research Center, and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund, PI13/00061 to Granada, regional governments of Spain (Andalucía, Asturias, Basque Country, Murcia [No. 6236], and Navarra), and Instituto San Carlos III Las Redes Temáticas de Investigación Cooperativa en Salud (RD06/0020; Spain); Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk, C570/A16491 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk; United Kingdom).