Abstract DP-014: LIFETIME NUMBER OF OVULATORY CYCLES ARE DIFFERENTIALLY ASSOCIATED WITH OVARIAN CANCER HISTOTYPES: AN ANALYSIS FROM THE OVARIAN CANCER COHORT CONSORTIUM (OC3)
Authors: Trabert Britton , Townsend Mary K. , Fortner Renée T. , Visvanathan Kala , Tworoger Shelley S. , Wentzensen Nicolas 
Published: June 2021

Abstract
BACKGROUND: Epidemiologic studies have consistently observed reduced ovarian cancer risks with higher parity and oral contraceptive use. Increased risks with younger age at menarche and older age at menopause have also been reported. Furthermore, it has been demonstrated that an acute pro-inflammatory environment is created following ovulation at the surface of the ovary and within the distal fallopian tube, whereby both are bathed in follicular fluid containing inflammatory cytokines, reactive oxygen species, and steroids, creating a DNA damage-rich environment and thereby supporting the possible role of incessant ovulation in ovarian carcinogenesis. Consistent with this, greater lifetime ovulatory cycles (LOC) have been associated with increased ovarian cancer risk in numerous studies, however the etiologic heterogeneity of this association has not been resolved. It is difficult to measure LOCs directly, but estimates of the cumulative sum of a woman's ovulatory cycles can be obtained through mathematical algorithms that calculate the time between menopause and menarche (menstrual span) and subtract anovulatory cycles, i.e., durations of oral contraceptive use and pregnancy.
AIM: To investigate the association of LOC and its components with ovarian cancer (overall and by histotype) using prospective individual-level data from the Ovarian Cancer Cohort Consortium (OC3).
METHODS: We analyzed data from 23 prospective cohort studies including 3,866 ovarian cancer cases diagnosed among 618,175 naturally menopausal women. Cases included 2288 serous, 352 endometrioid, 210 mucinous, and 137 clear cell tumors, and 879 other epithelial/unknown tumors. We evaluated associations between LOC, individual components of LOC (menstrual span, pregnancy, oral contraceptive use), and ovarian cancer using Cox regression stratified by study and adjusted for potential confounders; histotype analyses were conducted using competing-risks Cox regression.
RESULTS: In models evaluating the overall LOC effect (without adjustment for component factors), women in the 90th percentile of LOC (&gt;511) were almost twice as likely to be diagnosed with ovarian cancer during follow-up than women in the 10th percentile (&lt;295 cycles) [hazard ratio (HR) (95% confidence interval (CI): 1.92 (1.62-2.62)]. Per one-year increase in LOC (12 cycles), ovarian cancer risk was increased by 2.5% [1.025 (1.02-1.03)]. This association was heterogenous by histotype; a one-year increase in LOC was associated with increased risk of serous [1.026 (1.02-1.03)], endometrioid [1.04 (1.02-1.06)], and clear cell tumors [1.07 (1.04-1.10)], while no association was observed for mucinous tumors [1.00 (0.98-1.02), p-heterogeneity&lt;0.01]. Adjusting for LOC-components, pregnancy and oral contraceptive use, the LOC-ovarian cancer association remained but was attenuated [per year LOC: 1.014 (1.007-1.02)]. The associations were more similar across histotypes in adjusted models (1.02 serous, 1.03 endometrioid, 1.05 clear cell; p-values&lt;0.05), likely due to accounting for stronger risk reductions associated with prior pregnancy among endometrioid and clear cell tumors than serous tumors.
CONCLUSIONS: In this large prospective analysis of pooled cohort study data we observed positive associations between increased LOC and risk of serous, endometrioid, and clear cell tumors, independent of the associations with individual LOC components. Our data provide support for the hypothesis that incessant ovulation contributes to the etiology of these ovarian cancer histotypes, and further supports the etiologic heterogeneity of ovarian cancers.
Citation Format: Britton Trabert, Mary K. Townsend, Renée T. Fortner, Kala Visvanathan, Shelley S. Tworoger, Nicolas Wentzensen, on behalf of the Ovarian Cancer Cohort Consortium (OC3). LIFETIME NUMBER OF OVULATORY CYCLES ARE DIFFERENTIALLY ASSOCIATED WITH OVARIAN CANCER HISTOTYPES: AN ANALYSIS FROM THE OVARIAN CANCER COHORT CONSORTIUM (OC3) [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-014.