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)

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 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.

Figure 1.

The associations between total number of lifetime ovulatory cycles (LOC) and ovarian cancer risk among naturally menopausal women based on a 5-knot spline (knots at 10^th, 25^th, 50^th, 75^th and 90^th percentiles): pooled analysis of individual-level data from 20 cohort studies participating in the Ovarian Cancer Cohort Consortium (OC3).

Figure 2.

Graphical display of calculated values of total number of lifetime ovulatory cycles (LOC) among naturally postmenopausal women based on common reproductive characteristics, shading is based on LOC cutpoints corresponding to relative risk: low/blue (reference, hazard ratio=1.0), moderate/white (hazard ratio~1.4), and high/red (hazard ratio~2.0); and reflects the following range of absolute risks: lowest [blue,10-year absolute risk for 55-year-old woman: average 0.31% (min-max) (0.21–0.44)] and highest ovarian cancer risk (red:10-year absolute risk for 55-year-old woman: average 0.59% (min-max) (0.40–0.84)).