The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: An analysis from the Ovarian Cancer Cohort Consortium (OC3)

Britton Trabert, Shelley S. Tworoger, Katie M. O'Brien, Mary K. Townsend, Renee T. Fortner, Edwin S. Iversen, Patricia Hartge, Emily White, Pilar Amiano, Alan A. Arslan, Leslie Bernstein, Louise A. Brinton, Julie E. Buring, Laure Dossus, Gary E. Fraser, Mia M. Gaudet, Graham G. Giles, Inger T. Gram, Holly R. Harris, Judith Hoffman BoltonAnnika Idahl, Michael E. Jones, Rudolf Kaaks, Victoria A. Kirsh, Synnove F. Knutsen, Marina Kvaskoff, James V. Lacey, I. Min Lee, Roger L. Milne, N. Charlotte Onland-Moret, Kim Overvad, Alpa V. Patel, Ulrike Peters, Jenny N. Poynter, Elio Riboli, Kim Robien, Thomas E. Rohan, Dale P. Sandler, Catherine Schairer, Leo J. Schouten, Veronica W. Setiawan, Anthony J. Swerdlow, Ruth C. Travis, Antonia Trichopoulou, Piet A. Van Den Brandt, Kala Visvanathan, Lynne R. Wilkens, Alicja Wolk, Anne Zeleniuch-Jacquotte, Nicolas Wentzensen

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than womenin the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Original languageEnglish (US)
Pages (from-to)1210-1218
Number of pages9
JournalCancer Research
Volume80
Issue number5
DOIs
StatePublished - Mar 1 2020

Bibliographical note

Funding Information:
The Nurses' Health Study would like to acknowledge the Channing Division of Network Medicine and thank the following state cancer registries for their assistance: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The UKBGS thanks Breast Cancer Now and the Institute of Cancer Research (ICR) for support and funding. The ICR acknowledges National Health Service funding to the National Institute for Health Research Biomedical Research Centre. This work was supported by Department of Defense Ovarian Cancer Research Program grant W81XWH-12-1-0561. Additional research funding and support included the following: The intramural research program of the NCI, NIH, DHHS (Breast Cancer Detection and Demonstration Project Follow-up Study; NIH-AARP Diet and Health Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Study; Z01 CP010128); Intramural Research Program of the American Cancer Society (Cancer Prevention Study II); Breast Cancer Now and the Institute of Cancer Research (UKBGS, Generations Study); R01 CA077398 (California Teachers Study); R01 CA039742 (Iowa Women's Health Study); R01 CA164973 (Multiethnic Cohort); VicHealth and Cancer Council Victoria, and Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 (Melbourne Collaborative Cohort Study); UM1 CA186107, P01 CA087969, (Nurses' Health Study); UM1 CA182934, P30 CA016087 and P30 ES000260 (NYU Women's Health Study); NIEHS Intramural Research Program (Sisters Study, Project Z01-ES044005 to DPS); Swedish Research Council Grant VR 2017-00644 for the Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER) and the Swedish Cancer Foundation (Swedish Mammography Cohort); K22 CA193860 to HRH; K05CA154337 from the NCI and Office of Dietary Supplements (VITamins And Lifestyle Cohort); CA047988, HL043851, HL080467, HL099355, and CA182913 (Women's Health Study); and the coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Nordforsk (Norway); Health Research Fund (FIS), PI13/00061 to Granada; PI13/01162 to EPIC-Murcia, Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020; Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and V?sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford; United Kingdom).

Funding Information:
The Nurses' Health Study would like to acknowledge the Channing Division of Network Medicine and thank the following state cancer registries for their assistance: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The UKBGS thanks Breast Cancer Now and the Institute of Cancer Research (ICR) for support and funding. The ICR acknowledges National Health Service funding to the National Institute for Health Research Biomedical Research Centre. This work was supported by Department of Defense Ovarian Cancer Research Program grant W81XWH-12-1-0561. Additional research funding and support included the following: The intramural research program of the NCI, NIH, DHHS (Breast Cancer Detection and

Publisher Copyright:
© 2020 American Association for Cancer Research.

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