Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia

Abstract

Purpose: Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors.

Methods: Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2).

Results: Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90).

Conclusion: This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

FIG 1.

Summary RRs for the association between frequent aspirin use and ovarian cancer risk in OC3 and OCAC, overall and by key subgroups of interest. Number of studies included in subgroup-specific meta-analyses: endometriosis (n = 11), obesity (n = 16), family history of breast/ovarian cancer (n = 15 for no/ n = 16 for yes), parity (n = 17), duration of OC use (n = 16), tubal ligation (n = 14), and risk score (n = 17). Models were adjusted for age, parity, duration of oral contraceptive use, duration of menopausal hormone therapy use, and BMI. Models stratified by risk score were adjusted for age and duration of menopausal hormone therapy use. Participants with missing data on these covariates (< 10% for all covariates except duration of menopausal hormone therapy use) were retained in the models using missing indicators. We also conducted a complete case analysis and the results were unchanged. ^aP value for heterogeneity by study design. ^bP value for heterogeneity by subgroup. BMI, body mass index; OC, oral contraceptive; OC3, Ovarian Cancer Cohort Consortium; OCAC, Ovarian Cancer Association Consortium; RR, relative risk.

FIG 2.

Summary RRs for the associations between frequent aspirin use and each ovarian cancer histotype in OC3 and OCAC, overall and by key subgroups of interest. Tests for heterogeneity in the association across ovarian cancer histotypes: overall (P = .60), no endometriosis (P = .17), endometriosis (P = .31), no obesity (P = .13), obesity (P = .69), no family history of breast/ovarian cancer (P = .93), family history of breast/ovarian cancer (P = .64), parous (P = .39), nulliparous (P = .64), no OC use (P = .19), < 5 years of OC use (P = .62), 5+ years of OC use (P = .27), no tubal ligation (P = .35), tubal ligation (P = .74), ovarian cancer risk score = 0 (P = .96), ovarian cancer risk score = 1 (P = .79), and ovarian cancer risk score ≥ 2 (P = .42). Models were adjusted for age, parity, duration of oral contraceptive use, duration of menopausal hormone therapy use, BMI, and study. Models stratified by risk score were adjusted for age, duration of menopausal hormone therapy use, and study. For mucinous ovarian cancers, the RR for women with ovarian cancer risk score = 0 was unable to be estimated. BMI, body mass index; OC, oral contraceptive; OC3, Ovarian Cancer Cohort Consortium; OCAC, Ovarian Cancer Association Consortium; RR, relative risk.

FIG A1.

Meta-analysis of the overall association^a between frequent aspirin use and ovarian cancer risk in OC3 and OCAC. ^aAdjusted for age, parity, duration of oral contraceptive use, duration of menopausal hormone therapy use, and BMI. AARP, NIH-AARP Diet and Health Study; AUS, Australian Ovarian Cancer Study & Australian Cancer Study; BMI, body mass index; CPS2, Cancer Prevention Study II Nutrition Cohort; CTS, California Teachers Study, DOV, Diseases of the Ovary and their Evaluation Study; HAW, Hawaii Ovarian Cancer Study; HOP, Hormones and Ovarian Cancer Prediction Study; IWHS, Iowa Women's Health Study; NCO, North Carolina Ovarian Cancer Study; NHS, Nurses' Health Study; NHSII, Nurses' Health Study II; OC3, Ovarian Cancer Cohort Consortium; OCAC, Ovarian Cancer Association Consortium; PLCO, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; RR, relative risk; SISTERS, Sister Study; UCI, University of California, Irvine Ovarian Cancer Study; UKO, United Kingdom Ovarian Cancer Population Study; USC, University of Southern California, Study of Lifestyle and Women’s Health; VITAL, Vitamins and Lifestyle Cohort.