Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility

Key Points Question Is the association between frequent aspirin use and reduced risk of ovarian cancer modified by genetic susceptibility to ovarian cancer, assessed using a polygenic score (PGS)? Findings In this pooled analysis of 8 case-control studies from the Ovarian Cancer Association Consortium, including 4476 case patients and 6659 control participants, there was no evidence of effect modification by the PGS. Consistent associations between frequent aspirin use and reduced risk of ovarian cancer were observed for individuals with a PGS less than and greater than the median. Meaning The findings of this study suggest that frequent aspirin use may lower risk of ovarian cancer regardless of an individual’s genetic susceptibility to ovarian cancer.


Introduction
Ovarian cancer is a highly fatal gynecologic malignant neoplasm with few known modifiable risk factors. 1 Evidence suggests that aspirin may protect against the development of ovarian cancer, particularly when used frequently (daily or near daily). 2,3In a pooled analysis of 17 cohort and casecontrol studies, frequent aspirin use was associated with a 13% reduced risk of ovarian cancer, with no significant heterogeneity by study design or ovarian cancer histotype. 4ile aspirin is a promising chemopreventive agent for ovarian cancer, its use remains limited by several factors.First, serious adverse events can occur with aspirin use, including gastric ulcer and hemorrhagic stroke 5 ; although rare, these risks are nonnegligible.Second, the incidence of ovarian cancer in the general population is low; thus, the number needed to treat to prevent 1 case of ovarian cancer is high. 4Targeting chemoprevention programs to individuals at higher risk of ovarian cancer could reduce the number needed to treat and improve the benefit-harm profile. 6 previously investigated whether individuals at increased risk of ovarian cancer due to epidemiologic risk factors (endometriosis, obesity, family history of breast or ovarian cancer, nulliparity, no oral contraceptive use, no tubal ligation) might benefit from frequent aspirin use.We did not observe effect modification by these individual risk factors or an epidemiologic risk factor score calculated as the number of epidemiologic risk factors. 4In the current analysis, we expanded our evaluation to test whether the association of frequent aspirin use with ovarian cancer is modified by genetic susceptibility to ovarian cancer, assessed using a polygenic score (PGS) based on common genetic variants. 7

Study Design and Population
For this case-control study, we pooled data from the following 8 population-based case-control studies from the Ovarian Cancer Association Consortium (OCAC): the Australian Ovarian Cancer Study, 8 the Diseases of the Ovary and Their Evaluation Study, 9,10 the Hawaii Ovarian Cancer Study, 11,12 the Hormones and Ovarian Cancer Prediction Study, 13 the North Carolina Ovarian Cancer Study, 14,15 the University of California, Irvine Ovarian Cancer Study, 16 the UK Ovarian Cancer Population Study, 17 and the University of Southern California Study of Lifestyle and Women's Health 18 (eTable 1 in Supplement 1).][10][11][12][13][14][15][16][17][18] These 8 OCAC studies were included because they collected data on self-reported frequency of aspirin use, as described in eTable 1 in Supplement 1.For this analysis, frequent aspirin use (yes or no) was harmonized across the studies to indicate daily or almost daily use for 6 months or longer, to the extent possible.We focused specifically on frequent aspirin use, as this was the pattern of aspirin use most consistently associated with reduced ovarian cancer risk in prior analyses. 2,3Other covariates were harmonized as previously described. 2All participants provided either written informed consent or implicit consent through return of the study questionnaire.Participating studies obtained institutional review board (IRB) approval at their respective institutions, and the OCAC Coordinating Center (Duke University) received IRB approval from its institution and participating registries as required for data acquisition, pooling, and harmonization.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Within these 8 studies, 86% of case patients and control participants had genotype data available.Sample collection, genotyping, and quality control were conducted as described previously. 19Genetic susceptibility to ovarian cancer was summarized using a PGS previously developed within 63 OCAC studies and validated in external populations. 7We used the PGS developed using the stepwise method (22 single-nucleotide variants; eTable 2 in Supplement 1).
Because this PGS was developed for nonmucinous epithelial ovarian cancer, we only included case patients with nonmucinous cancer in our analysis (242 case patients were excluded).

JAMA Network Open | Oncology
Frequent Aspirin Use and Ovarian Cancer Risk According to Genetic Susceptibility

Statistical Analysis
We used logistic regression to estimate odds ratios (ORs) and 95% CIs for the associations between frequent aspirin use and nonmucinous ovarian cancer.

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Odds ratios (ORs) and 95% CIs were calculated from a logistic regression model adjusted for age, site, interaction between age and site, race and ethnicity, parity, duration of oral contraceptive use, menopausal status, and obesity (body mass index Ն30 kg/m 2 ).The OR for a 1-SD increase in PGS equals 1.32 (95% CI, 1.26-1.37).The P interaction between frequent aspirin use and PGS treated continuously is .43. a Low-grade serous ovarian cancers were excluded due to the low number of case patients.
b Adjusted for age, site, interaction between age and site, race and ethnicity, parity, duration of oral contraceptive use, menopausal status, and obesity.
c Interaction between frequent aspirin use and the PGS treated continuously.P heterogeneity by histotype equals 0.31 for individuals with a PGS less than the median and 0.26 for individuals with a PGS equal to or greater than the median.

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Frequent

Discussion
In this pooled analysis of 8 case-control studies, we observed consistent protective associations between frequent aspirin use and nonmucinous ovarian cancer across strata of genetic susceptibility to ovarian cancer.These results suggest that inherited genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not modify the protective association between frequent aspirin use and ovarian cancer.The only stratum with no protective association was individuals with a PGS greater than the 80th percentile, but the CI for the association in this stratum did not preclude a 13% risk reduction; given the overall lack of evidence for effect modification, the association for this subgroup will need to be assessed in additional studies before concluding that it is null.Risk reductions were otherwise maintained in individuals with a PGS greater than the median, including for high-grade serous and endometrioid cancers, suggesting that research could further evaluate subgroups of higher-risk individuals to improve the risk-benefit profile of aspirin for chemoprevention.Although we did not observe effect modification on the multiplicative scale, future prospective studies are needed to estimate the absolute benefit of frequent aspirin use for individuals at higher risk of ovarian cancer and to weigh the benefits and harms for all conditions affected by aspirin.

Limitations
This study has some limitations.The case-control design was retrospective and potentially limited by confounding and recall bias.However, we carefully adjusted for known potential confounders, and case-control and prospective cohort risk estimates of the association of aspirin with ovarian cancer were similar in our previous study, 4 suggesting minimal recall bias.We only included the subset of participants with genetic data available, but the association of aspirin with ovarian cancer was nearly identical in this subset and the full case-control population, 4 suggesting no systematic differences.
We were unable to test for effect modification by pathogenic variants (ie, BRCA1/BRCA2); randomized clinical trials of aspirin use in these specific subgroups are ongoing. 20This study leveraged harmonized genetic and epidemiologic data from 8 ovarian cancer studies, a data resource that allowed for assessment of the association of aspirin with ovarian cancer across strata of the PGS.
frequent aspirin use and reduced risk of ovarian cancer modified by genetic susceptibility to ovarian cancer, assessed using a polygenic score (PGS)?Findings In this pooled analysis of 8 case-control studies from the Ovarian Cancer Association Consortium, including 4476 case patients and 6659 control participants, there was no evidence of effect modification by the PGS.Consistent associations between frequent aspirin use and reduced risk of ovarian cancer were observed for individuals with a PGS less than and greater than the median.Meaning The findings of this study suggest that frequent aspirin use may lower risk of ovarian cancer regardless of an individual's genetic susceptibility to ovarian cancer.
Associations were estimated overall and by quantiles of the PGS based on the PGS distribution in the controls.Given the low prevalence of ovarian cancer, ORs were assumed to estimate the relative risk.The likelihood ratio test was used to test for statistical interaction.Polytomous logistic regression, with controls as the reference group, was used to estimate associations by ovarian cancer histotype.Models were adjusted for age (continuous), study site, interaction of age and site, self-reported race and ethnicity (Black, White, ResultsThis study included 4476 case patients and 6659 control participants.At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants.Case patients and control participants self-reported that they were Black (122 [3%] vs Figure.Associations Between Frequent Aspirin Use and Nonmucinous Epithelial Ovarian Cancer Risk Within Strata of Polygenic Score (PGS)

Table 2 .
Associations Between Frequent Aspirin Use and Nonmucinous Epithelial Ovarian Cancer Risk by Histotype Within Strata of Polygenic Score a Abbreviations: NA, not applicable; OR, odds ratio; PGS, polygenic score.