Abstract 854: Ovarian cancer risk factors by histologic subtypes: evidence for etiologic heterogeneity
Authors: Wentzensen Nicolas A. , Poole Elizabeth , Arslan Alan A. , Patel Alpa V. , Setiawan V Wendy , Visvanathan Kala , Weiderpass Elisabete , White Emily , Adami Hans-Olov , Brinton Louise A. , Bernstein Leslie , Buring Julie , Butler Lesley M. , Chamosa Saioa , Clendenen Tess V. , Dossus Laure , Fortner Renee , Gapstur Susan M. , Gaudet Mia M. , Gram Inger Torhild , Hartge Patricia , Hoffman-Bolton Judith , Idahl Annika , Jones Michael , Kaaks Rudolf , Kirsh Vivki , Koh Woon-Puay , Lacey James V. , Lee I-Min , Lundin Eva , Merritt Melissa , Peters Ulrike , Poynter Jenny , Rinaldi Sabina , Robien Kim , Rohan Thomas , Sandler Dale P. , Schouten Leo J. , Sjöholm Louise , Sieri Sabina , Swerdlow Anthony , Tjønneland Anne , Trabert Britton , Wilkens Lynne , Wolk Alicja , Yang Hannah P. , Zeleniuch-Jacquotte Anne , Tworoger Shelley S. 
Published: August 2015

Abstract
Background: A subset of high grade serous carcinomas may arise from the fallopian tube, while some endometrioid and clear cell carcinomas may derive from endometrial tissue. Previous studies have suggested differences in ovarian cancer risk factors by histologic subtypes, but had limited sample sizes. In the Ovarian Cancer Cohort Consortium (OC3), we evaluated associations of reproductive, hormonal, demographic and lifestyle factors, and family history of cancer with ovarian cancer subtypes. Identification of potential differences in associations among subtypes is important for clarifying ovarian cancer etiology and for developing novel prevention and risk prediction approaches.
Methods: Among over 1.2 million women from 21 cohort studies, 4,347 ovarian cancers with histology information were identified during follow-up (3223 serous, 555 endometrioid, 316 mucinous, 253 clear cell). We used competing risks Cox proportional hazards regression to compute risk factor associations by histologic subtype. Models were stratified on study and year of birth and adjusted for age, parity and oral contraceptive use; subtype heterogeneity was evaluated by a likelihood ratio test. Unsupervised hierarchical clustering was used to evaluate patterns of risk factors by histology.
Results: Most risk factors showed significant heterogeneity across histologic subtypes. Higher parity was most strongly associated with lower risks of endometrioid (RR per child: 0.79; 95%CI: 0.74-0.85) and clear cell (RR: 0.69; 95%CI: 0.61-0.78) carcinomas (p-het&lt;0.0001). Age at menopause was positively and tubal ligation was inversely associated only with endometrioid and clear cell carcinomas (p-het = 0.02 and 0.003, respectively). Long-term menopausal hormone use (&gt;5 years) was associated with endometrioid carcinomas (RR: 2.23; 95% CI: 1.46-3.42) and serous carcinomas (RR: 1.66; 95% CI: 1.44-1.92), and inversely associated with clear cell carcinomas (RR: 0.43; 95% CI: 0.20-0.91; p-het = 0.001). Family history of breast cancer was associated with increased risk of serous carcinomas (RR:1.13; 95% CI:1.02-1.27) and endometrioid carcinomas (RR: 1.44; 95% CI: 1.12-1.87; p-het = 0.02). Smoking (per 20 pack years) showed a positive association with mucinous carcinomas (RR: 1.38; 95% CI: 1.09-1.75) and an inverse association with clear cell carcinomas (RR:0.62; 95% CI: 0.46-0.85; p-het = 0.001). In unsupervised hierarchical clustering, serous and mucinous carcinomas clustered in one group and endometrioid and clear cell carcinomas in the other.
Conclusion: Our results demonstrate heterogeneous associations of risk factors with ovarian cancer subtypes, supporting the hypothesis that the subtypes develop through different pathways. Most established risk factors were more strongly associated with non-serous carcinomas, suggesting that risk prediction may be more challenging for serous cancers, the most fatal subtype.
Citation Format: Nicolas A. Wentzensen, Elizabeth Poole, Alan A. Arslan, Alpa V. Patel, V Wendy Setiawan, Kala Visvanathan, Elisabete Weiderpass, Emily White, Hans-Olov Adami, Louise A. Brinton, Leslie Bernstein, Julie Buring, Lesley M. Butler, Saioa Chamosa, Tess V. Clendenen, Laure Dossus, Renee Fortner, Susan M. Gapstur, Mia M. Gaudet, Inger Torhild Gram, Patricia Hartge, Judith Hoffman-Bolton, Annika Idahl, Michael Jones, Rudolf Kaaks, Vivki Kirsh, Woon-Puay Koh, James V. Lacey, I-Min Lee, Eva Lundin, Melissa Merritt, Ulrike Peters, Jenny Poynter, Sabina Rinaldi, Kim Robien, Thomas Rohan, Dale P. Sandler, Leo J. Schouten, Louise Sjöholm, Sabina Sieri, Anthony Swerdlow, Anne Tjønneland, Britton Trabert, Lynne Wilkens, Alicja Wolk, Hannah P. Yang, Anne Zeleniuch-Jacquotte, Shelley S. Tworoger. Ovarian cancer risk factors by histologic subtypes: evidence for etiologic heterogeneity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 854. doi:10.1158/1538-7445.AM2015-854