• Nicolas Wentzensen, Britton Trabert, Amanda Black, Louise A. Brinton, Patricia Hartge, Catherine Schairer, and Hannah P. Yang, National Cancer Institute; Dale P. Sandler, National Institute of Environmental Health Science, Bethesda, MD; Elizabeth M. Poole, Julie Buring, I-Min Lee, and Shelley S. Tworoger, Brigham and Women's Hospital; Elizabeth M. Poole, Hans-Olov Adami, Julie Buring, I-Min Lee, and Shelley S. Tworoger, Harvard University, Boston, MA; Emily White and Ulrike Peters, Fred Hutchinson Cancer Research Center, Seattle, WA; Alan A. Arslan, Tess V. Clendenen, and Anne Zeleniuch-Jacquotte, New York University School of Medicine; Thomas Rohan, Albert Einstein College of Medicine, New York, NY; Alpa V. Patel, Susan M. Gapstur, and Mia M. Gaudet, American Cancer Society, Atlanta, GA; V. Wendy Setiawan, University of Southern California, Los Angeles; Leslie Bernstein and James V. Lacey Jr, City of Hope, Duarte, CA; Kala Visvanathan and Judith Hoffman-Bolton, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Elisabete Weiderpass and Inger T. Gram, University of Tromsø-The Arctic University of Norway, Tromsø; Elisabete Weiderpass, Cancer Registry of Norway, Oslo, Norway; Elisabete Weiderpass, Hans-Olov Adami, Louise K. Sjöholm, and Alicja Wolk, Karolinska Institute; Stockholm; Annika Idahl and Eva Lundin, Umeå University, Umeå, Sweden; Elisabete Weiderpass, Folkhälsan Research Center, Helsinki, Finland; Lesley M. Butler, University of Pittsburgh, Pittsburgh, PA; Saioa Chamosa, BioDonostia Research Institute, San Sebastian, Spain; Laure Dossus, French Institute of Health and Medical Research, Paris; Sabina Rinaldi, International Agency for Research on Cancer, Lyon, France; Renee Fortner and Rudolf Kaaks, German Cancer Research Center, Heidelberg, Germany; Michael Jones and Anthony Swerdlow, The Institute of Cancer Research; Melissa A. Merritt, Imperial College of London, London; Ruth Travis, University of Oxford, Oxford, United Kingdom; Victoria

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; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). 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.