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).
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland. britton.trabert@nih.gov.
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
- Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, North Carolina.
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
- Department of Statistical Science, Duke University, Durham, North Carolina.
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain.
- New York University School of Medicine, NYU Langone Health, New York, New York.
- City of Hope, Duarte, California.
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
- IARC, Lyon, France.
- Loma Linda University, Loma Linda, California.
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
- Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, Baltimore, Maryland.
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden.
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
- CESP, Fac. de médecine-Univ. Paris-Sud, Fac. de médecine-UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.
- Department of Public Health, Aarhus University, Aarhus, Denmark.
- Division of Pediatric Epidemiology and Clinical Research, University of Minnesota, Minneapolis, Minnesota.
- School of Public Health, Imperial College London, United Kingdom.
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, D.C.
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
- University of Southern California, Los Angeles, California.
- Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
- Hellenic Health Foundation, Athens, Greece.
- Population Sciences in the Pacific Program (Cancer Epidemiology), University of Hawaii Cancer Center, Honolulu, Hawaii.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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 women in 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.