{"paper_id":"13c79a1d-03ea-448e-9122-792e561575f2","body_text":"original reports\nModification of the Association Between\nFrequent Aspirin Use and Ovarian Cancer Risk: A\nMeta-Analysis Using Individual-Level Data From\nTwo Ovarian Cancer Consortia\nLauren M. Hurwitz, PhD, MHS 1; Mary K. Townsend, ScD 2; Susan J. Jordan, PhD 3; Alpa V. Patel, PhD 4; Lauren R. Teras, PhD 4;\nJames V. Lacey Jr, PhD, MPH 5; Jennifer A. Doherty, PhD, MS 6; Holly R. Harris, PhD 7; Marc T. Goodman, PhD 8; Yurii B. Shvetsov, PhD 9;\nFrancesmary Modugno, MS, PhD, MPH 10,11; Kirsten B. Moysich, PhD, MS 12; Kim Robien, PhD 13; Anna Prizment, PhD 14;\nJoellen M. Schildkraut, PhD, MPH 15; Andrew Berchuck, MD 16;R e n´ee T. Fortner, PhD 17; Andrew T. Chan, MD, MPH 18,19;\nNicolas Wentzensen, MD, PhD, MS 20; Patricia Hartge, ScD 21; Dale P. Sandler, PhD 22; Katie M. O ’Brien, PhD 22;\nHoda Anton-Culver, PhD 23; Argyrios Ziogas, PhD 23; Usha Menon, MD 24; Susan J. Ramus, PhD 25,26; Celeste Leigh Pearce, PhD, MPH 27;\nAnna H. Wu, PhD, MPH 28; Emily White, PhD, MS 29; Ulrike Peters, PhD, MPH 29; Penelope M. Webb, DPhil 30;\nShelley S. Tworoger, PhD 2; and Britton Trabert, PhD, MS 1,31\nabstractPURPOSE Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has\ncomprehensively assessed for effect modi fication. We leveraged harmonized, individual-level data from 17\nstudies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across\nsubgroups of women with other ovarian cancer risk factors.\nMETHODS Nine cohort studies from the Ovarian Cancer Cohort Consortium (n 5 2,600 cases) and eight case-\ncontrol studies from the Ovarian Cancer Association Consortium (n 5 5,726 cases) were included. We used Cox\nregression and logistic regression to assess study-speci fic associations between frequent aspirin use ( $ 6 days/\nweek) and ovarian cancer risk and combined study-speci fic estimates using random-effects meta-analysis. We\nconducted analyses within subgroups de fined by individual ovarian cancer risk factors (endometriosis, obesity,\nfamily history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of\nrisk factors (0, 1, and $ 2).\nRESULTS Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20),\nwith no significant heterogeneity by study design ( P 5 .48) or histotype ( P 5 .60). Although no association was\nobserved among women with endometriosis, consistent risk reductions were observedamong all other subgroups\ndefined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, allP-heterogeneity. .05), including\nwomen with $ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90).\nCONCLUSION This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent\naspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer\nrisk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of\nprinciple that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.\nJ Clin Oncol 00. Published by American Society of Clinical Oncology\nINTRODUCTION\nOvarian cancer is the most fatal gynecologic cancer,\nlargely because of nonspeci fic symptom presenta-\ntion and lack of early detection strategies. 1 Chemo-\nprevention holds promise but remains an understudied\nparadigm to reduce ovarian cancer burden. 2 Chronic\ninflammation likely plays a key role in ovarian carcino-\ngenesis,3 as factors associated with epithelial disruption\nfrom ovulation,4,5 inflammation-related exposures such\nas endometriosis and pelvic in flammatory disease,6,7\nand circulating biomarkers of in flammation8,9 are\nassociated with ovarian cancer risk. Anti-in flammatory\nmedications such as aspirin may lower risk of ovarian\ncancer development via inhibition of the cyclooxygenase\nenzymes, leading to decreased synthesis of in flamma-\ntory mediators, or via cyclooxygenase-independent\npathways including inhibition of Wnt/ b-catenin and\nNF-kb.\n10\nA growing body of evidence supports a role of\naspirin in reducing ovarian cancer risk. Pooled\nsecondary analyses of randomized controlled trials\nof aspirin for cardiovascular disease prevention\nASSOCIATED\nCONTENT\nAppendix\nAuthor af filiations\nand support\ninformation (if\napplicable) appear\nat the end of this\narticle.\nAccepted on June 17,\n2022 and published at\nascopubs.org/journal/\njco on July 22, 2022:\nDOI https://doi.org/10.\n1200/JCO.21.01900\n1\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nhave noted a decreased risk of female reproductive\ncancers with $ 3 years of aspirin use, although too few\novarian cancer cases were diagnosed in these trial\npopulations to draw inferences for ovarian cancer\nspeci fically.\n11 In the observational setting, individual\nstudy results have been mixed, 12 -23 but meta-\nanalyses 24 and pooled analyses of cohort 25 and case-\ncontrol 26 studies have found that aspirin may reduce\novarian cancer risk by 10%-20%, particularly when\nused frequently (ie, daily or almost daily).\nHowever, although aspirin use appears to be one of the\nfew modi fiable protective factors for ovarian cancer,\npopulation-wide chemoprevention programs are generally\nconsidered infeasible because of the low incidence of\novarian cancer and the known risk of bleeding conferred by\nfrequent aspirin use.\n27 Instead, such programs will likely\nneed to focus on subgroups of women at elevated risk of\novarian cancer.\n28 Established factors that increase ovarian\ncancer risk include a family history of breast or ovarian\ncancer, endometriosis, and obesity, whereas factors that\ndecrease risk include parity, oral contraceptive use, and\ntubal ligation. Whether frequent aspirin use reduces risk of\novarian cancer among subgroups of women de fined by\nthese risk factors is unknown, and extremely large, well-\npowered studies are needed.\nIn this study, we leveraged harmonized, individual-level\ndata from two ovarian cancer consortia that previously\nreported on frequent aspirin and ovarian cancer risk\n25,26 to\ncomprehensively assess this association across key sub-\ngroups of interest. By meta-analyzing results from these 17\nstudies, we aimed to test for the consistency of the asso-\nciation across study design and personal characteristics\nand provide the most precise estimates of the aspirin-\novarian cancer association to date.\nMETHODS\nStudy Populations\nWe analyzed individual-level data from prospective cohort\nstudies from the Ovarian Cancer Cohort Consortium\n(OC3)\n29 and population-based case-control studies from\nthe Ovarian Cancer Association Consortium (OCAC).\nStudies were included if they collected information on\nfrequency of aspirin use; this resulted in the inclusion of\nnine cohort and eight case-control studies, a subset of the\nstudies included in previous aspirin analyses from these\nconsortia.\n25,26 The cohort studies (NIH-AARP Diet and\nHealth Study, 16,30 Cancer Prevention Study II Nutrition\nCohort,31,32 California Teachers Study, 33 Iowa Women ’s\nHealth Study, 19 Nurses’ Health Study, 18 Nurses’ Health\nStudy II, 18 Prostate, Lung, Colorectal, and Ovarian Cancer\nScreening Trial,34 Sister Study,35 and Vitamins and Lifestyle\nCohort36,37) were all US-based cohorts; our analysis in-\ncluded women from these cohorts with at least one intact\novary, no history of cancer at baseline, and nonmissing age\nand frequency of aspirin use. The case-control studies\n(Australian Ovarian Cancer Study,\n22 Diseases of the Ovary\nand their Evaluation Study, 23,38 Hawaii Ovarian Cancer\nStudy,39,40 Hormones and Ovarian Cancer Prediction\nStudy,41 North Carolina Ovarian Cancer Study, 42,43 Uni-\nversity of California, Irvine Ovarian Cancer Study, 44\nUnited Kingdom Ovarian Cancer Population Study, 45\nUniversity of Southern California, and Study of Lifestyle\nand Women ’s Health 46) were from the United States,\nUnited Kingdom, and Australia.\nAll participating studies obtained institutional review board\napproval at their respective institutions. Participants pro-\nvided written informed consent or implicit consent through\nreturn of study questionnaires. The coordinating centers for\nOC3 (Brigham and Women ’s Hospital, Harvard T. H. Chan\nSchool of Public Health) and OCAC (Duke University)\nCONTEXT\nKey Objective\nTo determine whether the association between frequent aspirin use and ovarian cancer risk is modi fied by established\novarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, parity, oral contraceptive use,\nand tubal ligation).\nKnowledge Generated\nIn combined analyses of individual participant data from 17 study populations, frequent aspirin use was associated with a\n13% reduction in ovarian cancer risk overall. Consistent risk reductions were observed across most subgroups of women\nwith other ovarian cancer risk factors, with the exception of endometriosis. Among women with two or more risk factors,\nfrequent aspirin use was associated with a 19% reduction in ovarian cancer risk.\nRelevance\nThis study con firms the association of frequent aspirin use with decreased risk of ovarian cancer. The use of aspirin for\novarian cancer chemoprevention may best be targeted to higher-risk women with two or more ovarian cancer risk factors,\nto maximize the population-level bene fit/risk ratio.\n2 Published by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nreceived institutional review board approval from their in-\nstitutions and participating registries as required for data\nacquisition, pooling, and harmonization.\nStudy Variables\nGiven previous findings that frequent aspirin use was most\nstrongly associated with ovarian cancer risk,\n25,26 our\nprimary exposure was frequent aspirin use, which was\nself-reported in all included studies (Appendix Tables A1\nand A2, online only). Frequent aspirin use was harmo-\nnized across the study popula tions to indicate aspirin\nuse for $ 6 days/week or $ 28 days/month and for a\nduration of $ 6 months. Frequent aspirin use was de fined\nirrespective of dose, as few studies collected data on\naspirin dose. Women who re ported less frequent or no\naspirin use were combined to form the reference group.\nOther covariates were centrally harmonized at the coor-\ndinating centers of OC3 and OCAC.\n6,29,47-49 For the cohort\nstudies, aspirin use and other covariates were assessed at\nenrollment or at a subsequ ent questionnaire cycle,\nwhich then became the baseline for this analysis. For the\ncase-control studies, covariates were ascertained at\nenrollment.\nOur primary outcome was invasive epithelial ovarian, fal-\nlopian tube, or peritoneal cancer. In the cohort studies,\ncases were identified through linkage to cancer registries or\nmedical chart review.\n29 Nonepithelial tumors and tumors of\nlow malignant potential/borderline were excluded. Case\nascertainment for the case-control studies included linkage\nto cancer registries or hospital registries, surgical treatment\ncenters, gynecologic oncology centers, physician of fices,\nand/or pathology databases.\n47 We also examined associ-\nations for the most common ovarian cancer histotypes,\nincluding high-grade serous, mucinous, endometrioid,\nclear cell, and other epithelial tumors. Very few low-grade\nserous tumors were observed in these study populations;\nthese tumors were consequently excluded from histotype-\nspecific analyses.\nStatistical Analysis\nFor each cohort study, hazar d ratios (HRs) and 95% CIs\ncomparing frequent aspirin use to nonfrequent use were\ncalculated using Cox proportional hazards regression.\nWomen entered the analysis at age at study entry\nand contributed person-time until first diagnosis of ovarian\ncancer, death, or end of follow-up. Models were adjusted\nfor baseline age, number of full-term births (none, one,\ntwo, three, or $ four), duration of oral contraception use\n(never, # 1, . 1-5, . 5-10, or . 10 years), duration\nof menopausal hormone therapy use (premenopausal,\nnever, # 5, . 5-10, or . 10 years), and body mass\nindex (BMI, , 20, 20 to , 25, 25 to , 30, 30 to , 35, or\n$ 35 kg/m\n2). For each case-control study, odds ratios\n(ORs) and 95% CIs were calculated using logistic re-\ngression, adjusting for the same covariates. Study-speci fic\nHRs and ORs were calculated overall as well as for\nsubgroups de fined by age at baseline (cohort studies) or\ndiagnosis/index date (case-control studies; , 50, 50-59,\n60-69, or $ 70 years), history of endometriosis (yes or no),\nobesity (BMI $ 30 or , 30 kg/m\n2), parity (parous or\nnulliparous), family history of breast or ovarian cancer\n(yes or no), duration of oral contraceptive use (never, , 5,\nor $ 5 years), tubal ligation (yes or no), and nonaspirin\nnonsteroidal anti-in flammatory drug (NSAID) use (yes or\nno). Study-speci fic effect estimates, overall and for each\nsubgroup, were combined using random effects meta-\nanalysis to generate summary relative risks (RRs).\nWe also calculated RRs within subgroups de fined by an\novarian cancer risk score (range, 0-6, categorized as 0, 1,\nand $ 2), with each ovarian cancer risk factor (endome-\ntriosis, obesity, nulliparity, family history of breast or ovarian\ncancer, no oral contraceptive use, and no tubal ligation)\ncontributing one point to this score. Before using this score,\nwe con firmed that the risk score was positively associated\nwith ovarian cancer risk (RR for a score of 1 v 0: 1.20, 95%\nCI, 1.10 to 1.30; RR for a score of $ 2 v 0: 1.78, 95% CI,\n1.64 to 1.94). Risk score analyses were adjusted for age\nand duration of menopausal hormone therapy use.\nTo examine associations by ovarian cancer histotype, we\nconducted competing risks Cox regression using an aug-\nmented data approach with the pooled cohort data,\n50 and\npolytomous logistic regression with the pooled case-control\ndata,\n51,52 adjusting for study and the same covariates as\nabove. We conducted pooled instead of study-speci fic\nanalyses because of the smaller number of events by\nhistotype. The results from the cohort and case-control\nanalyses were combined using random effects meta-\nanalysis.\nWe examined heterogeneity in effect estimates by study,\nstudy design, subgroup, and histotype using Cochran ’sQ\ntests.\n53 The number needed to treat (NNT) to prevent one\novarian cancer was calculated using the observed 10-year\nabsolute risk of ovarian cancer among nonaspirin users in\nthe cohort studies and the combined cohort and case-\ncontrol summary RRs.\n54 All statistical tests were two-sided,\nand P values , .05 were considered statistically significant.\nStudy-specific and pooled analyses were conducted in SAS\n9.4, meta-analyses were conducted using the meta com-\nmand in Stata 16, and figures were generated in R 4.0.2.\nRESULTS\nIn the nine cohort studies, there were 491,651 women at\nrisk. The mean age at baseline ranged from 46.0 to\n68.2 years, mean follow-up ranged from 4.6 to 14.3 years,\nand the prevalence of frequent aspirin use ranged from\n9.8% to 38%. During follow-up, 2,600 women were di-\nagnosed with incident ovarian cancer (56% high-grade\nserous, 2% low-grade serous, 9% endometrioid, 5%\nclear cell, 4% mucinous, and 23% other/unknown epi-\nthelial). Across the eight case-control studies, there were\nJournal of Clinical Oncology 3\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\n5,726 cases (54% high-grade serous, 4% low-grade se-\nrous, 15% endometrioid, 9% clear cell, 5% mucinous, and\n13% other/unknown epithelial) and 8,027 controls. The\nmedian age of the cases ranged from 56.2 to 60.7 years,\nand the prevalence of frequent aspirin use ranged from\n5.6% to 29.8%. Additional characteristics of the study\npopulations are described in Appendix Tables A1 and A2.\nOverall, frequent aspirin use was associated with a 10%\nreduction in ovarian cancer risk in the cohort studies\n( H R ,0 . 9 0 ;9 5 %C I ,0 . 8 1t o1 . 0 1 )a n da1 6 %r e d u c e dr i s k\nin the case-control studies (OR, 0.84; 95%, CI, 0.72 to\n0.98, Appendix Fig A1 ,o n l i n eo n l y ) .M e t a - a n a l y z i n gt h e\ncohort and case-control studies yielded an overall\nsummary RR of 0.87 (95% CI, 0.80 to 0.94), with no\ndifference between the cohort and case-control study\nresults ( P-heterogeneity 5 .48).\nUsing the combined cohort and case-control data, when we\nexamined associations within subgroups defined by factors\nthat increase ovarian cancer risk, we observed possible\neffect modi fication by history of endometriosis ( Fig 1 ).\nAmong women without endometriosis, frequent aspirin use\nwas associated with reduced ovarian cancer risk (RR, 0.82;\n95% CI, 0.73 to 0.92), whereas no risk reduction was ob-\nserved among women with endometriosis (RR, 1.15; 95%\nCI, 0.80 to 1.65; P-heterogeneity5 .08). However, the CI for\nthe latter effect estimate was large because of the small\nnumber of women with endometriosis (prevalence range,\n1%-9% in the cohort studies, 3%-11% among OCAC\ncontrols). Frequent aspirin use was associated with lower\novarian cancer risk regardless of obesity, although the as-\nsociation was slightly stronger among obese women (RR,\n0.79; 95% CI, 0.67 to 0.93) than among nonobese women\nGroup\nOverall\nEndometriosis\n  No\n  Yes\nObesity\n  No\n  Yes\nFamily history\n  No\n  Yes\nNulliparity\n  No\n  Yes\nDuration of OC use, years\n  Never\n  < 5\n  ≥ 5\nTubal ligation\n  No\n  Yes\nOvarian cancer risk score\n  0\n  1\n  2+\nRR (95% CI)\n0.87 (0.80 to 0.94)\n0.82 (0.73 to 0.92)\n1.15 (0.80 to 1.65)\n0.91 (0.80 to 1.03)\n0.79 (0.67 to 0.93)\n0.86 (0.79 to 0.94)\n0.88 (0.72 to 1.06)\n0.88 (0.81 to 0.96)\n0.83 (0.64 to 1.09)\n0.86 (0.77 to 0.96)\n0.92 (0.75 to 1.12)\n0.91 (0.77 to 1.08)\n0.82 (0.73 to 0.91)\n0.93 (0.76 to 1.13)\n0.97 (0.79 to 1.19)\n0.93 (0.82 to 1.06)\n0.81 (0.73 to 0.90)\nI2\n10.7\n7.4\n0.0\n35.4\n0.0\n0.0\n2.6\n0.0\n22.5\n0.0\n30.6\n0.0\n5.2\n5.5\n56.4\n1.7\n0.0\nPa\n.48\n.94\n.68\n.11\n.22\n.37\n.88\n.23\n.55\n.92\n.18\n.63\n.54\n.15\n.13\n.31\n.72\nPb\n.08\n.18\n.88\n.71\n.79\n.27\n.20\n0.75 1.0 1.25 1.5\nRR\nFIG 1. Summary RRs for the association between frequent aspirin use and ovarian cancer risk in OC3 and OCAC,\noverall and by key subgroups of interest. Number of studies included in subgroup-speci fic meta-analyses: en-\ndometriosis (n 5 11), obesity (n 5 16), family history of breast/ovarian cancer (n 5 15 for no/ n 5 16 for yes), parity\n(n 5 17), duration of OC use (n 5 16), tubal ligation (n 5 14), and risk score (n 5 17). Models were adjusted for age,\nparity, duration of oral contraceptive use, duration of menopausal hormone therapy use, and BMI. Models strati fied\nby risk score were adjusted for age and duration of menopausal hormone therapy use. Participants with missing\ndata on these covariates ( , 10% for all covariates except duration of menopausal hormone therapy use) were\nretained in the models using missing indicators. We also conducted a complete case analysis and the results were\nunchanged.\naP value for heterogeneity by study design. bP value for heterogeneity by subgroup. BMI, body mass\nindex; OC, oral contraceptive; OC3, Ovarian Cancer Cohort Consortium; OCAC, Ovarian Cancer Association\nConsortium; RR, relative risk.\n4 Published by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\n(RR, 0.91; 95% CI, 0.80 to 1.03; P-heterogeneity 5 .18).\nAssociations were similar across strata of family history of\nbreast or ovarian cancer (RR, 0.86; 95% CI, 0.79 to 0.94 for\nwomen without a family history, RR, 0.88; 95% CI, 0.72 to\n1.06 for women with a family history,P-heterogeneity5 .88).\nConsistent risk reductions were observed within subgroups\ndefined by protective factors for ovarian cancer, including\nparity ( P-heterogeneity 5 .71), duration of oral contra-\nceptive use ( P-heterogeneity 5 .79), and tubal ligation\n(P-heterogeneity 5 .27, Fig 1 ). There was also no effect\nmodification by nonaspirin NSAID use (RR, 0.86; 95% CI,\n0.77 to 0.95 for no NSAID use, RR, 0.86; 95% CI, 0.75 to\n0.98 for NSAID use, P-heterogeneity 5 .95).\nWe did not observe effect modification by age at enrollment\nin the cohort ( P-heterogeneity 5 .78) or case-control\n(P-heterogeneity 5 .26) studies ( Table 1 ). However, in\nthe case-control studies, there was possible strengthening\nof the association with age, with the strongest inverse as-\nsociation observed among women age 70 years or older at\ndiagnosis/enrollment (OR, 0.72; 95% CI, 0.57 to 0.91).\nIn general, associations with frequent aspirin use were\nsimilar for all ovarian cancer histotypes ( Fig 2 , Appendix\nTable A3 , online only). Risk reductions were particularly\nrobust for high-grade serous ovarian cancer, both overall\n(RR, 0.86; 95% CI, 0.78 to 0.94) and across subgroups\ndefined by ovarian cancer risk factors. For women with\nendometriosis, although there was no association between\nfrequent aspirin use and ovarian cancer overall, there was\nsuggestion of an inverse association with endometrioid\novarian cancer, the histotype most strongly associated with\nendometriosis.\nIn the cohort studies, 21% of women had none of the six\novarian cancer risk factors, 42% had one risk factor, and\n37% had $ two. In the case-control studies, the corre-\nsponding percentages of women with zero, one, and $ two\nrisk factors were 8%, 28%, and 64% for cases, and 12%,\n37%, and 51% for controls. In analyses strati fied by the\nnumber of risk factors (ie, the ovarian cancer risk score),\nfrequent aspirin use was inversely associated with ovarian\ncancer risk among women at higher risk of ovarian cancer\nbecause of the presence of $ two risk factors (RR, 0.81;\n95% CI, 0.73 to 0.90, Fig 1). The protective association for\nthese higher-risk women was consistent across histotypes\n(Fig 2, Appendix Table A3, P-heterogeneity 5 .42). Among\nthe higher-risk women, the NNT to prevent one ovarian\ncancer within 10 years was 970 (95% CI, 683 to 1,843,\nAppendix Table A4, online only). By contrast, the NNT for\nall women in the study population regardless of risk score\nwas 1784 (95% CI, 1,160 to 3,866).\nDISCUSSION\nIn this analysis of data from two ovarian cancer consortia,\nfrequent aspirin use was associated with a 13% reduction\nin ovarian cancer risk overall. A similar risk reduction was\nobserved for high-grade serous ovarian cancer, the most\ncommon and one of the most fatal histotypes, which is\nimportant because most established risk factors are more\nweakly associated with high-grade serous ovarian can-\ncers.\n6 The consistency of the frequent aspirin use-ovarian\ncancer association across the individual case-control and\ncohort study populations was notable and provides strong\nTABLE 1. Summary Relative Risks for the Association Between Frequent Aspirin Use and Ovarian Cancer Risk in OC3 and OCAC, by Subgroups De fined by\nAge at Study Enrollment\nAge, years No. of Studies Included I 2 % RR 95% CI P (heterogeneity by study design) P (heterogeneity by subgroup)\nCohort studies\n, 50 2 0.0 0.99 0.49 to 2.00 — .78\n50-59 9 0.0 0.87 0.69 to 1.09 —\n60-69 8 0.0 0.88 0.76 to 1.02 —\n$ 70 6 26.7 1.05 0.76 to 1.46 —\nCase-control studies\n, 50 7 9.7 1.11 0.76 to 1.63 — .26\n50-59 8 46.5 0.91 0.66 to 1.24 —\n60-69 8 0.0 0.81 0.67 to 0.97 —\n$ 70 8 0.0 0.72 0.57 to 0.91 —\nAll studies\n, 50 9 0.0 1.09 0.79 to 1.49 .77 .56\n50-59 17 0.0 0.87 0.75 to 1.02 .82\n60-69 16 0.0 0.85 0.76 to 0.95 .46\n$ 70 14 23.8 0.86 0.69 to 1.06 .07\nNOTE. Models were adjusted for age, parity, duration of oral contraceptive use, duration of menopausal hormone therapy use, and BMI.\nAbbreviations: BMI, body mass index; OC3, Ovarian Cancer Cohort Consortium; OCAC, Ovarian Cancer Association Consortium; RR, relative risk.\nJournal of Clinical Oncology 5\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nHigh-Grade Serous\nOverall\nEndometriosis\n  No\n  Yes\nObesity\n  No\n  Yes\nFamily history\n  No\n  Yes\nNulliparity\n  No\n  Yes\nDuration of OC use, years\n  Never\n  < 5\n  ≥ 5\nTubal ligation\n  No\n  Yes\nOvarian cancer risk score\n  0\n  1\n  2+\nRR\nEndometrioid\nOverall\nEndometriosis\n  No\n  Yes\nObesity\n  No\n  Yes\nFamily history\n  No\n  Yes\nNulliparity\n  No\n  Yes\nDuration of OC use, years\n  Never\n  < 5\n  ≥ 5\nTubal ligation\n  No\n  Yes\nOvarian cancer risk score\n  0\n  1\n  2+\nRR\nClear Cell\nOverall\nEndometriosis\n  No\n  Yes\nObesity\n  No\n  Yes\nFamily history\n  No\n  Yes\nNulliparity\n  No\n  Yes\nDuration of OC use, years\n  Never\n  < 5\n  ≥ 5\nTubal ligation\n  No\n  Yes\nOvarian cancer risk score\n  0\n  1\n  2+\nRR\nMucinous\nOverall\nEndometriosis\n  No\n  Yes\nObesity\n  No\n  Yes\nFamily history\n  No\n  Yes\nNulliparity\n  No\n  Yes\nDuration of OC use, years\n  Never\n  < 5\n  ≥ 5\nTubal ligation\n  No\n  Yes\nOvarian cancer risk score\n  0\n  1\n  2+\n0.25 0.50 1.0 2.0 0.25 0.50 1.0 2.0\n0.25 0.50 1.0 2.0 0.25 0.50 1.0 2.0\nRR\nFIG 2. (Continued).\n6 Published by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nsupport for a bene ficial effect of frequent aspirin use on\novarian cancer risk.\nImportantly, our study also found that established ovarian\ncancer risk factors do not modify the association between\nfrequent aspirin use and ovarian cancer risk. There was a\nsuggestion of effect modi fication by endometriosis, with an\ninverse association observed for women without but not\nwith self-reported endometriosis, but this was likely driven\nby the small number of women with endometriosis and the\nlimited power to detect associations within this subgroup.\nAdditionally, there was no effect modification by endometriosis for\nendometrioid or clear cell tumors, the two specific histotypes for\nwhich endometriosis is a risk factor.6\nRisk reductions associated with frequent aspirin use were\notherwise consistent across subgroups de fined by factors\nthat increase (obesity and family history of breast/ovarian\ncancer) and decrease (parity, oral contraceptive use, and\ntubal ligation) ovarian cancer risk. The lack of effect mod-\nification by adiposity is particularly notable, given that other\nstudies have reported aspirin to be more weakly associated\nOther/Unknown Epithelial\nOverall\nEndometriosis\n  No\n  Yes\nObesity\n  No\n  Yes\nFamily history\n  No\n  Yes\nNulliparity\n  No\n  Yes\nDuration of OC use, years\n  Never\n  < 5\n  ≥ 5\nTubal ligation\n  No\n  Yes\nOvarian cancer risk score\n  0\n  1\n  2+\n0.25 0.50 1.0 2.0\nRR\nFIG 2. (Continued). Summary RRs for the associations between frequent\naspirin use and each ovarian cancer histotype in OC3 and OCAC, overall and\nby key subgroups of interest. Tests for heterogeneity in the association across\novarian cancer histotypes: overall (P 5 .60), no endometriosis (P 5 .17),\nendometriosis (P 5 .31), no obesity ( P 5 .13), obesity ( P 5 .69), no\nfamily history of breast/ovarian cancer ( P 5 .93), family history of breast/\novarian cancer (P 5 .64), parous (P 5 .39), nulliparous (P 5 .64), no OC use\n(P 5 .19), , 5 years of OC use (P 5 .62), 51 years of OC use (P 5 .27), no\ntubal ligation (P 5 .35), tubal ligation (P 5 .74), ovarian cancer risk score5 0\n(P 5 .96), ovarian cancer risk score5 1( P 5 .79), and ovarian cancer risk\nscore $ 2( P 5 .42). Models were adjusted for age, parity, duration of oral\ncontraceptive use, duration of menopausal hormone therapy use, BMI, and\nstudy. Models strati fied by risk score were adjusted for age, duration of\nmenopausal hormone therapy use, and study. For mucinous ovarian cancers,\nthe RR for women with ovarian cancer risk score 5 0 was unable to be\nestimated. BMI, body mass index; OC ,o r a lc o n t r a c e p t i v e ;O C 3 ,O v a r i a n\nCancer Cohort Consortium; OCAC, Ovarian Cancer Association Consortium;\nRR, relative risk.\nJournal of Clinical Oncology 7\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nwith reduced cardiovascular disease and colorectal cancer\nrisk55,56 and more strongly associated with reduced endo-\nmetrial cancer risk 57 among obese individuals; this could\nsuggest that aspirin ’s mechanism of action for preventing\ncardiovascular disease and these other cancers may differ\nfrom that preventing ovarian cancer.\nThere was possible effect modification by the ovarian cancer\nrisk score, with a null association observed among women\nwith zero ovarian cancer risk factors. However, the results for\nwomen with zero risk factors were inconclusive, given the\nsmall number of cases and heterogeneity in the study-\nspecific results for this subgroup. More critically, we ob-\nserved a clear inverse associat ion between frequent aspirin\nuse and ovarian cancer among women with multiple ovarian\ncancer risk factors. These results are important, given that\nany implementation of aspir in use for ovarian cancer che-\nmoprevention will likely need to focus on speci fic high-risk\nsubgroups.\n28 Our study suggests that frequent aspirin use is\nprotective among women at increased risk of ovarian cancer\nbecause of the presence of established epidemiologic risk\nfactors, with a lower NNT among women with$ 2 risk factors,\nand that targeting chemoprevention programs to women with\nepidemiologic risk factors may thus be a viable strategy.\nTo our knowledge, this study is the largest to date on aspirin\nand ovarian cancer risk and the first to examine effect\nmodification by a comprehensive set of ovarian cancer risk\nfactors. Previous studies of aspirin, examined alone or\ncombined with other NSAIDs, have also reported no effect\nmodification by BMI,\n17,18 parity,12,16,18,46 or oral contraceptive\nuse,16,18,46 but these individual studies were only powered to\ndetect very strong differences. One study observed a pos-\nsible stronger association between daily aspirin use and\novarian cancer risk with increasing BMI,\n58 a trend that was\nmirrored in our study, although our study suggests that\nfrequent aspirin may still be modestly protective among\nnonobese women. Our study con firms and expands upon\nthese prior studies by combining the existing observational\ndata, which facilitated a well-powered analysis, even among\nsubgroups. Access to the individual-level data from each\nstudy allowed us to apply a standardized analytic approach,\nassess associations by histotype, and focus speci fically on\nfrequent aspirin use, the pattern of use that appears most\nprotective against ovarian cancer.\n25,26\nAlthough we combined results across study design, such\npooling was necessary to obtain suf ficient power to test for\neffect modi fication. Moreover, formal comparison of the\ncohort and case-control results revealed no meaningful or\nstatistically signi ficant differences. There may have been\nsome bias because of the use of observational data, but\nresearch has found that observational studies of aspirin and\ncancer can recapitulate randomized controlled trial findings\nwhen there is detailed recording of aspirin use and careful\nadjustment for confounders.\n59 We were unable to examine\nassociations speci fically for low-dose aspirin, which has\nbeen more strongly associated with reduced ovarian cancer\nrisk in prior studies,\n13,26 but frequent aspirin use was highly\ncorrelated with low-dose use in the studies with dosage\ninformation available (r 5 0.97 in OC3, r 5 0.82 in OCAC\ncontrols). We did not have data on indication for aspirin use\nor age at initiation of use, both of which require further study.\nWe did not look at associations among women at increased\nrisk of ovarian cancer because of common or rare genetic\nvariants as genetic data were not available for all included\nstudies; whether aspirin reduces risk among women with\nhighly penetrant mutations (ie, BRCA1/BRCA2 or Lynch\nsyndrome) will require examination in specialized study\npopulations. Finally, when calculating the NNT, we were\nunable to incorporate associations for precise durations of\naspirin use because of the use of observational data. The\nNNT also does not account for the known risks associated\nwith frequent aspirin use, and further research on the net\nbenefits and harms is needed.\nIn conclusion, this study, the largest to date on frequent\naspirin use and ovarian cancer, supports a 13% reduction in\novarian cancer risk with frequent aspirin use, with a 14%\nreduction for high-grade serous carcinoma, the most\ncommon and one of the more lethal histotypes. Similar risk\nreductions were observed across subgroups de fined by\nestablished epidemiologic risk factors, and no subgroup\nexperienced a signi ficant increased risk with aspirin use.\nThese results suggest that primary prevention of ovarian\ncancer is an added benefit of frequent aspirin use that could\nbe incorporated into composite risk-bene fit calculations.\nGiven that women with elevated ovarian cancer risk because\nof epidemiologic risk factors also benefit and that the NNT to\nprevent one ovarian cancer is lower for higher-risk women,\nfuture work should explore how chemoprevention programs\nwith aspirin could complement existing preventive strategies,\nwhich are currently limited to women with the highest risk (ie,\nprophylactic salpingo-oophorectomy for BRCA1/2 carriers)\nand target additional high-risk subgroups to maximize\npopulation-level impact and minimize risks.\nAFFILIATIONS\n1Division of Cancer Epidemiology and Genetics, National Cancer\nInstitute, Rockville, MD\n2Department of Cancer Epidemiology, H. Lee Mof fitt Cancer Center and\nResearch Institute, Tampa, FL\n3School of Public Health, University of Queensland, Brisbane,\nQueensland, Australia\n4Department of Population Science, American Cancer Society,\nAtlanta, GA\n5Department of Computational and Quantitative Medicine, Beckman\nResearch Institute, City of Hope Comprehensive Cancer Center,\nDuarte, CA\n6Department of Population Health Sciences, Huntsman Cancer Institute,\nUniversity of Utah, Salt Lake City, UT\n8 Published by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\n7Program in Epidemiology, Division of Public Health Sciences, Fred\nHutchinson Cancer Research Center, Seattle, WA\n8Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical\nCenter, Los Angeles, CA\n9Cancer Epidemiology Program, University of Hawaii Cancer Center,\nHonolulu, HI\n10Department of Obstetrics, Gynecology, and Reproductive Sciences,\nUniversity of Pittsburgh School of Medicine, Pittsburgh, PA\n11Department of Epidemiology, Graduate School of Public Health,\nUniversity of Pittsburgh, Pittsburgh, PA\n12Department of Cancer Prevention and Control, Roswell Park\nComprehensive Cancer Center, Buffalo, NY\n13Department of Exercise and Nutrition Sciences, Milken Institute\nSchool of Public Health, George Washington University, Washington, DC\n14Division of Hematology, Oncology and Transplantation, University of\nMinnesota Masonic Cancer Center, University of Minnesota,\nMinneapolis, MN\n15Department of Epidemiology, Emory University Rollins School of Public\nHealth, Atlanta, GA\n16Division of Gynecologic Oncology, Duke University Medical Center,\nDurham, NC\n17Division of Cancer Epidemiology, German Cancer Research Center\n(DKFZ), Heidelberg, Germany\n18Clinical and Translational Epidemiology Unit, Massachusetts General\nHospital, Boston, MA\n19Division of Gastroenterology, Massachusetts General Hospital,\nBoston, MA\n20Division of Cancer Epidemiology and Genetics, National Cancer\nInstitute, Rockville, MD\n21Division of Cancer Epidemiology and Genetics, National Cancer\nInstitute, Rockville, MD\n22Epidemiology Branch, National Institute of Environmental Health\nSciences, Research Triangle Park, NC\n23Department of Epidemiology, University of California Irvine, Irvine, CA\n24MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology,\nUniversity College London, London, UK\n25School of Women ’s and Children ’s Health, Faculty of Medicine,\nUniversity of NSW Sydney, Sydney, Australia\n26Adult Cancer Program, Lowy Cancer Research Centre, University of\nNSW Sydney, Sydney, Australia\n27Department of Epidemiology, University of Michigan School of Public\nHealth, Ann Arbor, MI\n28Department of Preventive Medicine, Keck School of Medicine,\nUniversity of Southern California, Los Angeles, CA\n29Cancer Prevention Program, Division of Public Health Sciences, Fred\nHutchinson Cancer Research Center, Seattle, WA\n30Population Health Department, QIMR Berghofer Medical Research\nInstitute, Brisbane, Queensland, Australia\n31Department of Obstetrics and Gynecology, University of Utah,\nHuntsman Cancer Institute, Salt Lake City, UT\nCORRESPONDING AUTHOR\nLauren M. Hurwitz, PhD, MHS, 9609 Medical Center Dr, Rm 6E-588,\nRockville, MD 20850; Twitter: @LaurenMHurwitz;\ne-mail: lauren.hurwitz@nih.gov.\nDISCLAIMER\nThe content is solely the responsibility of the authors and does\nnot necessarily represent the of ficial views of the National Institutes\nof Health. This is a US Government work. There are no restrictions on\nits use.\nSUPPORT\nThis study was funded by US Department of Defense Ovarian Cancer Research\nProgram (W81XWH-19-1-0346). The OC3 received support from the US\nDepartment of Defense Ovarian Cancer Research Program (W81XWH-12-1-\n0561, W81XWH-19-1-0346) and the Intramural Research Program of the\nNational Cancer Institute at the National Institutes of Health. The Ovarian\nCancer Association Consortium was supported by a grant from the Ovarian\nCancer Research Fund thanks to donations by the family and friends of Kathryn\nSladek Smith. The Australian Ovarian Cancer Study and Australian Cancer\nStudy were funded by the US Army Medical Research and Material Command\n(DAMD17-01-1-0729), National Health and Medical Research Council of\nAustralia (199600, 400413), Cancer Councils of New South Wales, Victoria,\nQueensland, South Australia, and Tasmania, Cancer Foundation of Western\nAustralia. All aspects of the Cancer Prevention Study II were funded by the\nIntramural Research Program of the American Cancer Society and by the\nNational Cancer Institute at the National Institutes of Health Intramural\nResearch Program. The California Teachers Study and the research reported in\nthis publication were supported by National Cancer Institute at the National\nInstitutes of Health (grant numbers U01 CA199277, P30 CA033572, P30\nCA023100, UM1 CA164917, and R01 CA077398). The Diseases of the\nOvary and their Evaluation Study was funded by R01 CA112523 and R01\nCA87538. The Hawaii Ovarian Cancer Case–Control Study was funded by R01\nCA58598, N01 CN55424, and N01 PC67001. The Hormones and Ovarian\nCancer Prediction Study was funded by R01 CA95023 and Department of\nDefense (DOD) grant DAMD17-02-1-0669. The Iowa Women’s Health Study\nwas funded by the National Cancer Institute at the National Institutes of Health\n(R01 CA39742). The North Carolina Ovarian Cancer Study was funded by R01\nCA76016 and the DOD grant DAMD17-02-1-0666. The Nurses’ Health Study\nand Nurses’ Health Study II were funded by the National Cancer Institute at the\nNational Institutes of Health (UM1 CA186107, P01 CA87969, R01\nCA49449, U01 CA176726, and R01 CA67262). The NIH-AARP Diet and\nHealth Study was funded by the Intramural Research Program of the National\nCancer Institute at the National Institutes of Health. PLCO was funded through\ncontracts administered by the Division of Cancer Prevention at the National\nCancer Institute, National Institutesof Health, with support from the National\nCancer Institute Intramural Research Program. The Sister Study was funded by\nIntramural Research Program of the National Institute of Environmental Health\nSciences at the National Institutes of Health (Z01ES044005). The University\nof California, Irvine Ovarian Cancer Study was funded by R01 CA58860, R01\nCA92044, PSA 042205, and the Lon V Smith Foundation grant LVS-39420.\nThe United Kingdom Ovarian Cancer Population Study was funded by Cancer\nResearch UK, the Eve Appeal, and the OAK Foundation. The University of\nSouthern California, Study of Lifestyle and Women’s Health was funded by\nR01 CA17054, R01 CA14089, R01 CA61132, N01-PC-67010, P01\nCA17054, California Cancer Research Program (00-01389V-20170, R03\nCA113148, R03 CA115195, N01 CN25403), and California Cancer\nResearch Program (2II0200; USC). The Vitamins and Lifestyle Study was\nfunded by the National Cancer Institute and Office of Dietary Supplements at\nthe National Institutes of Health (K05 CA154337).\nAUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF\nINTEREST\nDisclosures provided by the authors are available with this article at DOI\nhttps://doi.org/10.1200/JCO.21.01900.\nAUTHOR CONTRIBUTIONS\nConception and design: Nicolas Wentzensen, Hoda Anton-Culver, Argyrios\nZiogas, Shelley S. Tworoger, Britton Trabert\nFinancial support: Francesmary Modugno, Britton Trabert\nAdministrative support: Mary K. Townsend, Andrew Berchuck, Shelley S.\nTworoger, Britton Trabert\nProvision of study materials or patients: Lauren R. Teras, Jennifer A.\nDoherty, Marc T. Goodman, Francesmary Modugno, Kim Robien, Joellen\nM. Schildkraut, Andrew T. Chan, Nicolas Wentzensen, Dale P. Sandler,\nHoda Anton-Culver, Susan J. Ramus, Celeste Leigh Pearce, Anna H. Wu,\nUlrike Peters, Penelope M. Webb, Shelley S. Tworoger, Britton Trabert\nCollection and assembly of data: Mary K. Townsend, Susan J. Jordan, Alpa\nV. Patel, Lauren R. Teras, Marc T. Goodman, Yurii B. Shvetsov,\nJournal of Clinical Oncology 9\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nFrancesmary Modugno, Kirsten B. Moysich, Kim Robien, Joellen M.\nSchildkraut, Andrew Berchuck, Andrew T. Chan, Nicolas Wentzensen,\nPatricia Hartge, Dale P. Sandler, Hoda Anton-Culver, Argyrios Ziogas,\nUsha Menon, Susan J. Ramus, Celeste Leigh Pearce, Anna H. Wu, Emily\nWhite, Ulrike Peters, Penelope M. Webb, Shelley S. Tworoger, Britton\nTrabert\nData analysis and interpretation: Lauren M. Hurwitz, Susan J. Jordan,\nJennifer A. Doherty, Holly R. Harris, Marc T. Goodman, Kim Robien, Anna\nPrizment, Andrew Berchuck, Ren ´ee T. Fortner, Andrew T. Chan, Nicolas\nWentzensen, Patricia Hartge, Hoda Anton-Culver, Argyrios Ziogas, Ulrike\nPeters, Penelope M. Webb, Shelley S. Tworoger, Britton Trabert\nManuscript writing: All authors\nFinal approval of manuscript: All authors\nAccountable for all aspects of the work: All authors\nACKNOWLEDGMENT\nThe authors would like to thank the following state cancer registries for\ntheir help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME,\nMD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX,\nVA, WA, and WY. The authors assume full responsibility for analyses and\ninterpretation of these data. The authors would like to acknowledge the\nChanning Division of Network Medicine, Department of Medicine,\nBrigham and Women ’s Hospital, as the home of the Nurses ’ Health\nStudy. The collection of cancer incidence data used in the California\nTeachers Study was supported by the California Department of Public\nHealth pursuant to California Health and Safety Code Section 103885;\nCenters for Disease Control and Prevention ’s National Program of Cancer\nRegistries, under cooperative agreement 5NU58DP006344; the\nNational Cancer Institute ’s Surveillance, Epidemiology and End Results\nProgram under contract HHSN261201800032I awarded to the\nUniversity of California, San Francisco, contract HHSN261201800015I\nawarded to the University of Southern California, and contract\nHHSN261201800009I awarded to the Public Health Institute. The\nopinions, findings, and conclusions expressed herein are those of the\nauthor(s) and do not necessarily re flect the of ficial views of the State of\nCalifornia, Department of Public Health, the National Cancer Institute,\nthe National Institutes of Health, the Centers for Disease Control and\nPrevention or their contractors and subcontractors, or the regents of the\nUniversity of California, or any of its programs.\nThe Australian Ovarian Cancer Study Management Group (D. Bowtell, G.\nChenevix-Trench, A. deFazio, D. Gertig, A. Green, and P. Webb) and\nAustralian Cancer Study investigators (A. Green, P. Parsons, N. Hayward,\nP. Webb, and D. Whiteman) thank all the clinical and scienti fic\ncollaborators (see http://www.aocstudy.org/) and the women for their\ncontribution. Some of this work was undertaken at University College\nLondon Hospital/University College London, which received a proportion\nof funding from the Department of Health ’s National Institutes for Health\nResearch Biomedical Research Centre funding scheme. The authors\nparticularly thank I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan,\nJ. Ford, and N. Balogun for their contribution to the study. Support for\ntitle page creation and format was provided by AuthorArranger, a tool\ndeveloped at the National Cancer Institute. AOCS Study Group members\nare listed at Appendix 1 (online only).\nREFERENCES\n1. American Cancer Society: Cancer Facts & Figures 2021. Atlanta, GA, 2021. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/\ncancer-facts-figures-2021.html\n2. Kathawala RJ, Kudelka A, Rigas B: The chemoprevention of ovarian cancer: The need and the options. Curr Pharmacol Rep 4:250-260, 2018\n3. 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Ready A, Velicer CM, McTiernan A, et al: NSAID use and breast cancer risk in the VITAL cohort. Breast Cancer Res Treat 109:533-543, 2008\n38. Rossing MA, Cushing-Haugen KL, Wicklund KG, et al: Menopausal hormone therapy and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarker s Prev\n16:2548-2556, 2007\n39. Goodman MT, Lurie G, Thompson PJ, et al: Association of two common single-nucleotide polymorphisms in the CYP19A1 locus and ovarian cancer risk. E ndocr\nRelat Cancer 15:1055-1060, 2008\n40. Lurie G, Wilkens LR, Thompson PJ, et al: Combined oral contraceptive use and epithelial ovarian cancer risk: Time-related effects. Epidemiology19:237-243, 2008\n41. Ness RB, Dodge RC, Edwards RP, et al: Contraception methods, beyond oral contraceptives and tubal ligation, and risk of ovarian cancer. Ann Epidemiol 21:188-196, 2011\n42. Moorman PG, Calingaert B, Palmieri RT, et al: Hormonal risk factors for ovarian cancer in premenopausal and postmenopausal women. Am J Epidemiol 1 67:\n1059-1069, 2008\n43. Schildkraut JM, Iversen ES, Wilson MA, et al: Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer. PLoS\nOne 5:e10061, 2010\n44. Ziogas A, Gildea M, Cohen P, et al: Cancer risk estimates for family members of a population-based family registry for breast and ovarian cancer. Ca ncer\nEpidemiol Biomarkers Prev 9:103-111, 2000\n45. Balogun N, Gentry-Maharaj A, Wozniak EL, et al: Recruitment of newly diagnosed ovarian cancer patients proved challenging in a multicentre bioba nking study.\nJ Clin Epidemiol 64:525-530, 2011\n46. Wu AH, Pearce CL, Tseng CC, et al: Markers of in flammation and risk of ovarian cancer in Los Angeles County. Int J Cancer 124:1409-1415, 2009\n47. Pearce CL, Templeman C, Rossing MA, et al: Association between endometriosis and risk of histological subtypes of ovarian cancer: A pooled analys is of case-\ncontrol studies. Lancet Oncol 13:385-394, 2012\n48. Olsen CM, Nagle CM, Whiteman DC, et al: Obesity and risk of ovarian cancer subtypes: Evidence from the Ovarian Cancer Association Consortium. Endo cr Relat\nCancer 20:251-262, 2013\n49. Sieh W, Salvador S, McGuire V, et al: Tubal ligation and risk of ovarian cancer subtypes: A pooled analysis of case-control studies. Int J Epidemiol42:579-589, 2013\n50. Lunn M, McNeil D: Applying Cox regression to competing risks. Biometrics 51:524-532, 1995\n51. Dubin N, Pasternack BS: Risk assessment for case-control subgroups by polychotomous logistic regression. Am J Epidemiol 123:1101-1117, 1986\n52. Zabor EC, Begg CB: A comparison of statistical methods for the study of etiologic heterogeneity. Stat Med 36:4050-4060, 2017\n53. Borenstein M, Hedges LV, Higgins JPT, et al: Subgroup Analyses, Introduction to Meta-Analysis, Chichester, UK, John Wiley & Sons, 2009\n54. Altman DG, Andersen PK: Calculating the number needed to treat for trials where the outcome is time to an event. BMJ 319:1492-1495, 1999\n55. Ardeshna D, Khare S, Jagadish PS, et al: The dilemma of aspirin resistance in obese patients. Ann Transl Med 7:404, 2019\n56. Rothwell PM, Cook NR, Gaziano JM, et al: Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: Analysis of indi vidual\npatient data from randomised trials. Lancet 392:387-399, 2018\n57. Webb PM, Na R, Weiderpass E, et al: Use of aspirin, other nonsteroidal anti-in flammatory drugs and acetaminophen and risk of endometrial cancer: The\nEpidemiology of Endometrial Cancer Consortium. Ann Oncol 30:310-316, 2019\n58. Hurwitz LM, Michels KA, Cook MB, et al: Associations between daily aspirin use and cancer risk across strata of major cancer risk factors in two larg e U.S.\ncohorts. Cancer Causes Control 26:020-01357, 2020\n59. Algra AM, Rothwell PM: Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observa tional\nstudies versus randomised trials. Lancet Oncol 13:518-527, 2012\n60. Altman DG: Con fidence intervals for the number needed to treat. BMJ 317:1309-1312, 1998\nnnn\nJournal of Clinical Oncology 11\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nAUTHORS ’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nModification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer\nConsortia\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless othe rwise noted.\nRelationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.\nFor more information about ASCO ’s con flict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians ( Open Payments ).\nAlpa V. Patel\nResearch Funding: GRAIL (Inst)\nJoellen M. Schildkraut\nPatents, Royalties, Other Intellectual Property: Patent related treatment of\nPAD (peripheral arterial disease)(I)\nAndrew Berchuck\nHonoraria: Clovis Oncology, Merck, Tesaro, Premier Research\nResearch Funding: Novadaq Technologies\nTravel, Accommodations, Expenses: Merck\nAndrew T. Chan\nConsulting or Advisory Role: Pfizer, Boehringer Ingelheim, Bayer\nResearch Funding: Zoe Ltd, P fizer\nCeleste Leigh Pearce\nStock and Other Ownership Interests: SAVA, ANVS\nHonoraria: ViiV Healthcare (I)\nConsulting or Advisory Role: ViiV Healthcare (I)\nSpeakers' Bureau: ViiV Healthcare (I)\nResearch Funding: CytoDyn (I)\nUsha Menon\nStock and Other Ownership Interests: Abcodia\nResearch Funding: Abcodia (Inst)\nPatents, Royalties, Other Intellectual Property: Patent no: EP10178345.4 for\nBreast Cancer Diagnostics\nUncompensated Relationships: ILOF (Inst), Dana-Farber Cancer Institute (Inst),\nRNA Guardian (Inst), Micronoma (Inst)\nPenelope M. Webb\nResearch Funding: AstraZeneca (Inst)\nShelley S. Tworoger\nResearch Funding: BMS (Inst)\nNo other potential con flicts of interest were reported.\nPublished by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nAPPENDIX 1. AOCS STUDY GROUP\nManagement Group : D. Bowtell (Peter MacCallum Cancer Centre,\nMelbourne, Victoria, Australia; Department of Pathology, University of\nMelbourne, Parkville, Victoria, Australia; Sir Peter MacCallum Cancer\nCentre Department of Oncology, University of Melbourne, Parkville,\nVictoria, Australia; Department of Biochemistry and Molecular Biology,\nUniversity of Melbourne, Parkville, Victoria, Australia; Ovarian Cancer\nAction Research Centre, Department of Surgery and Cancer, Imperial\nCollege London, London, England, United Kingdom), G. Chenevix-\nTrench (QIMR Berghofer Medical Research Institute, Brisbane,\nQueensland, Australia), A. Green (QIMR Berghofer Medical Research\nInstitute, Brisbane, Queensland, Australia), P. Webb (QIMR Berghofer\nMedical Research Institute, Brisbane, Queensland, Australia), A.\nDeFazio (Centre for Cancer Research, The Westmead Institute for\nMedical Research, Sydney, New South Wales, Australia; The Uni-\nversity of Sydney, Sydney, New South Wales, Australia; Department of\nGynecological Oncology, Westmead Hospital, Sydney, New South\nWales, Australia), D. Gertig (Melbourne School of Population and\nGlobal Health, University of Melbourne, Parkville, Victoria, Australia)\nProject and Data Managers : N. Tra ficante (Peter MacCallum Cancer\nCentre, Melbourne, Victoria, Australia; Sir Peter MacCallum Cancer\nCentre Department of Oncology, University of Melbourne, Parkville,\nVictoria, Australia), S. Fereday (Peter MacCallum Cancer Centre,\nMelbourne, Victoria, Australia; Sir Peter MacCallum Cancer Centre\nDepartment of Oncology, University of Melbourne, Parkville, Victoria,\nAustralia), S. Moore (QIMR Berghofer Medical Research Institute,\nBrisbane, Queensland, Australia), J. Hung (Centre for Cancer Re-\nsearch, The Westmead Institute for Medical Research, Sydney, New\nSouth Wales, Australia), K. Harrap (QIMR Berghofer Medical Research\nInstitute, Brisbane, Queensland, Australia), T. Sadkowsky (QIMR\nBerghofer Medical Research Institute, Brisbane, Queensland, Aus-\ntralia), N. Pandeya (QIMR Berghofer Medical Research Institute,\nBrisbane, Queensland, Australia), Research Nurses and Assistants: M\nMalt (QIMR Berghofer Medical Research Institute, Brisbane,\nQueensland, Australia), A. Mellon (John Hunter Hospital, Lookout\nRoad, New Lambton, New South Wales, Australia), R. Robertson (John\nHunter Hospital, Lookout Road, New Lambton, New South Wales,\nAustralia), T. Vanden Bergh (Royal Hospital for Women, Barker Street,\nRandwick, New South Wales, Australia), M. Jones (Royal Hospital for\nWomen, Barker Street, Randwick, New South Wales, Australia), P.\nMackenzie (Royal Hospital for Women, Barker Street, Randwick, New\nSouth Wales, Australia), J. Maidens (Royal North Shore Hospital,\nReserve Road, St Leonards, New South Wales, Australia), K. Nattress\n(Royal Prince Alfred Hospital, Missenden Road, Camperdown, New\nSouth Wales, Australia), Y.E. Chiew (Centre for Cancer Research, The\nWestmead Institute for Medical Research, Sydney, New South Wales,\nAustralia), A. Stenlake (Department of Gynecological Oncology,\nWestmead Hospital, Sydney, New South Wales, Australia), H. Sullivan\n(Department of Gynecological Oncology, Westmead Hospital, Sydney,\nNew South Wales, Australia), B. Alexander (QIMR Berghofer Medical\nResearch Institute, Brisbane, Queensland, Australia), P. Ashover\n(QIMR Berghofer Medical Research Institute, Brisbane, Queensland,\nAustralia), S. Brown (QIMR Berghofer Medical Research Institute,\nBrisbane, Queensland, Australia), T. Corrish (QIMR Berghofer Medical\nResearch Institute, Brisbane, Queensland, Australia), L. Green (QIMR\nBerghofer Medical Research Institute, Brisbane, Queensland, Aus-\ntralia), L. Jackman (QIMR Berghofer Medical Research Institute,\nBrisbane, Queensland, Australia), K. Ferguson (QIMR Berghofer\nMedical Research Institute, Brisbane, Queensland, Australia), K.\nMartin (QIMR Berghofer Medical Research Institute, Brisbane,\nQueensland, Australia), A. Martyn (QIMR Berghofer Medical Research\nInstitute, Brisbane, Queensland, Australia), B. Ranieri (QIMR\nBerghofer Medical Research Institute, Brisbane, Queensland, Aus-\ntralia), J. White (Royal Adelaide Hospital, North Terrace, Adelaide,\nSouth Australia, Australia), V. Jayde (Royal Hobart Hospital, 48 Liv-\nerpool St, Hobart, Tasmania, Australia), P. Mamers (Monash Medical\nCentre, Clayton, Victoria, Australia), L. Bowes (Peter MacCallum\nCancer Centre, Melbourne, Victoria, Australia), L. Galletta (Peter\nMacCallum Cancer Centre, Melbourne, Victoria, Australia), D. Giles\n(Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia),\nJ. Hendley (Peter MacCallum Cancer Centre, Melbourne, Victoria,\nAustralia), K. Alsop (Peter MacCallum Cancer Centre, Melbourne,\nVictoria, Australia), T. Schmidt (Western Australian Research Tissue\nNetwork (WARTN), St John of God Pathology, Osborne Park, Western\nAustralia, Australia), H. Shirley (Western Australian Research Tissue\nNetwork (WARTN), St John of God Pathology, Osborne Park, Western\nAustralia, Australia), C. Ball (Women and Infant ’s Research Foun-\ndation, King Edward Memorial Hospital, Subiaco, Western Australia,\nAustralia), C. Young (Women and Infant ’s Research Foundation, King\nEdward Memorial Hospital, Subiaco, Western Australia, Australia), S.\nViduka (Western Australian Research Tissue Network (WARTN), St\nJohn of God Pathology, Osborne Park, Western Australia, Australia),\nHoa Tran (Western Australian Research Tissue Network [WARTN], St\nJohn of God Pathology, Osborne Park, Western Australia, Australia),\nSanela Bilic (Western Australian Research Tissue Network (WARTN),\nSt John of God Pathology, Osborne Park, Western Australia, Australia),\nLydia Glavinas (Western Australian Research Tissue Network\n(WARTN), St John of God Pathology, Osborne Park, Western Australia,\nAustralia), Julia Brooks (St John of God Hospital, Subiaco, Western\nAustralia, Australia), Clinical and Scienti fic Collaborators: R. Stuart-\nHarris (Canberra Hospital, Garran, Australian Capitol Territory, Aus-\ntralia), F. Kirsten (Bankstown Cancer Centre, Bankstown Hospital,\nBankstown, New South Wales, Australia), J. Rutovitz (Northern\nHaematology & Oncology Group, Integrated Cancer Centre, Wah-\nroonga, New South Wales, Australia), P. Clingan (Illawarra Shoalhaven\nLocal Health District, Wollongong Hospital, Wollongong, New South\nWales, Australia), A. Glasgow (Illawarra Shoalhaven Local Health\nDistrict, Wollongong Hospital, Wollongong, New South Wales, Aus-\ntralia), A. Proietto (John Hunter Hospital, Lookout Road, New\nLambton, New South Wales, Australia), S. Braye (John Hunter Hos-\npital, Lookout Road, New Lambton, New South Wales, Australia), G.\nOtton (John Hunter Hospital, Lookout Road, New Lambton, New South\nWales, Australia), J. Shannon (Nepean Hospital, Kingswood, New\nSouth Wales, Australia), T. Bonaventura (Newcastle Mater Miser-\nicordiae Hospital, Waratah, New South Wales, Australia), J. Stewart\n(Newcastle Mater Misericordiae Hospital, Waratah, New South Wales,\nAustralia), S. Begbie (Port Macquarie Base Hospital, Port Macquarie,\nNew South Wales, Australia) M. Friedlander (Prince of Wales Clinical\nSchool, University of New South Wales, New South Wales, Australia),\nD. Bell (Royal North Shore Hospital, Reserve Road, St Leonards, New\nSouth Wales, Australia), S. Baron- Hay (Royal North Shore Hospital,\nReserve Road, St Leonards, New South Wales, Australia), A. Ferrier\n(Royal North Shore Hospital, Reserve Road, St Leonards, New South\nWales, Australia) (dec), G. Gard (Royal North Shore Hospital, Reserve\nRoad, St Leonards, New South Wales, Australia), D. Nevell (Royal\nNorth Shore Hospital, Reserve Road, St Leonards, New South Wales,\nAustralia), N. Pavlakis (Royal North Shore Hospital, Reserve Road, St\nLeonards, New South Wales, Australia), S. Valmadre (Royal North\nShore Hospital, Reserve Road, St Leonards, New South Wales, Aus-\ntralia), B. Young (Royal North Shore Hospital, Reserve Road, St\nLeonards, New South Wales, Australia), C. Camaris (Royal Hospital for\nWomen, Barker Street, Randwick, New South Wales, Australia), R.\nCrouch (Royal Hospital for Women, Barker Street, Randwick, New\nSouth Wales, Australia), L. Edwards (Royal Hospital for Women, Barker\nStreet, Randwick, New South Wales, Australia), N. Hacker (Royal\nHospital for Women, Barker Street, Randwick, New South Wales,\nAustralia), D. Marsden (Royal Hospital for Women, Barker Street,\nRandwick, New South Wales, Australia), G. Robertson (Royal Hospital\nfor Women, Barker Street, Randwick, New South Wales, Australia), P.\nBeale (Royal Prince Alfred Hospital, Missenden Road, Camperdown,\nNew South Wales, Australia), J. Beith (Royal Prince Alfred Hospital,\nMissenden Road, Camperdown, New South Wales, Australia), J. Carter\n(Royal Prince Alfred Hospital, Missenden Road, Camperdown, New\nSouth Wales, Australia), C. Dalrymple (Royal Prince Alfred Hospital,\nMissenden Road, Camperdown, New South Wales, Australia), R.\nHoughton (Royal Prince Alfred Hospital, Missenden Road, Camper-\ndown, New South Wales, Australia), P. Russell (Royal Prince Alfred\nHospital, Missenden Road, Camperdown, New South Wales, Aus-\ntralia), M. Links (St George Hospital, Kogarah, New South Wales,\nJournal of Clinical Oncology\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nAustralia), J. Grygiel (St Vincent ’s Hospital, Darlinghurst, New South\nWales, Australia), J. Hill (Wagga Wagga Base Hospital, Wagga Wagga,\nNew South Wales, Australia), A. Brand (The University of Sydney,\nSydney, New South Wales, Australia; Crown Princess Mary Cancer\nCentre, Westmead Hospital, Sydney, New South Wales, Australia), K.\nByth (Crown Princess Mary Cancer Centre, Westmead Hospital,\nSydney, New South Wales, Australia), R. Jaworski (Department of\nPathology, Westmead Clinical School, Westmead Hospital, The Uni-\nversity of Sydney, New South Wales, Australia), P. Harnett (The\nUniversity of Sydney, Sydney, New South Wales, Australia; Crown\nPrincess Mary Cancer Centre, Westmead Hospital, Sydney, New South\nWales, Australia), R. Sharma (The University of Sydney, Sydney, New\nSouth Wales, Australia; Department of Pathology, Westmead Clinical\nSchool, Westmead Hospital, The University of Sydney, New South\nWales, Australia), G. Wain (Crown Princess Mary Cancer Centre,\nWestmead Hospital, Sydney, New South Wales, Australia), B. Ward\n(Mater Misericordiae Hospital, South Brisbane, Queensland, Aus-\ntralia), D. Papadimos (Mater Misericordiae Hospital, South Brisbane,\nQueensland, Australia), A. Crandon (The Royal Brisbane and Women’s\nHospital, Herston, Queensland, Australia), M. Cummings (The Royal\nBrisbane and Women ’s Hospital, Herston, Queensland, Australia), K.\nHorwood (The Royal Brisbane and Women ’s Hospital, Herston,\nQueensland, Australia), A. Obermair (The Royal Brisbane and\nWomen’s Hospital, Herston, Queensland, Australia), L. Perrin (The\nRoyal Brisbane and Women ’s Hospital, Herston, Queensland, Aus-\ntralia), D. Wyld (The Royal Brisbane and Women ’s Hospital, Herston,\nQueensland, Australia), J. Nicklin (The Royal Brisbane and Women ’s\nHospital, Herston, Queensland, Australia; Wesley Hospital, 451\nAuchenflower, Queensland, Australia), M. Davy (Royal Adelaide\nHospital, North Terrace, Adelaide, South Australia, Australia), M.K.\nOehler (Royal Adelaide Hospital, North Terrace, Adelaide, South\nAustralia, Australia), C. Hall (Royal Adelaide Hospital, North Terrace,\nAdelaide, South Australia, Australia), T. Dodd (Royal Adelaide Hos-\npital, North Terrace, Adelaide, South Australia, Australia), T. Healy\n(Burnside Hospital, Toorak Gardens, South Australia, Australia), K.\nPittman (Burnside Hospital, Toorak Gardens, South Australia, Aus-\ntralia), D. Henderson (Burnside Hospital, Toorak Gardens, South\nAustralia, Australia), J. Miller (Queen Elizabeth Hospital, Woodville\nSouth, South Australia, Australia), J. Pierdes (Queen Elizabeth Hos-\npital, Woodville South, South Australia, Australia), P. Blom field (Royal\nHobart Hospital, 48 Liverpool St, Hobart, Tasmania, Australia), D.\nChallis (Royal Hobart Hospital, 48 Liverpool St, Hobart, Tasmania,\nAustralia), R. McIntosh (Royal Hobart Hospital, 48 Liverpool St,\nHobart, Tasmania, Australia), A. Parker (Royal Hobart Hospital,\nHobart, Tasmania, Australia), B. Brown (Freemasons Hospital, 20 East\nMelbourne, Victoria, Australia), R. Rome (Freemasons Hospital,\nVictoria, Australia), D. Allen (Mercy Hospital for Women, Heidelberg,\nVictoria, Australia), P. Grant (Mercy Hospital for Women, Heidelberg,\nVictoria, Australia), S. Hyde (Mercy Hospital for Women, Heidelberg,\nVictoria, Australia), R. Laurie (Mercy Hospital for Women, Heidelberg,\nVictoria, Australia), M. Robbie (Mercy Hospital for Women, Heidelberg,\nVictoria, Australia), D. Healy (Monash Medical Centre, Clayton, Vic-\ntoria, Australia), T. Jobling (Monash Medical Centre, Clayton, Victoria,\nAustralia), T. Manolitsas (Monash Medical Centre, Clayton, Victoria,\nAustralia), J. McNealage (Monash Medical Centre, Clayton, Victoria,\nAustralia), P. Rogers (Monash Medical Centre, Clayton, Victoria,\nAustralia), B. Susil (Monash Medical Centre, 246 Clayton Rd, Clayton,\nVictoria, Australia), E. Sumithran (Monash Medical Centre, Clayton,\nVictoria, Australia), I. Simpson (Monash Medical Centre, 246 Clayton\nRd, Clayton, Victoria, Australia), K. Phillips (Peter MacCallum Cancer\nCentre, Melbourne, Victoria, Australia), D. Rischin (Peter MacCallum\nCancer Centre, Melbourne, Victoria, Australia), S. Fox (Peter Mac-\nCallum Cancer Centre, Melbourne, Victoria, Australia), D. Johnson\n(Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia), S.\nLade (Peter MacCallum Cancer Centre, Melbourne, Victoria, Aus-\ntralia), M. Loughrey (Peter MacCallum Cancer Centre, Melbourne,\nVictoria, Australia), N. O ’Callaghan (Peter MacCallum Cancer Centre,\nMelbourne, Victoria, Australia), W. Murray (Peter MacCallum Cancer\nCentre, Melbourne, Victoria, Australia), P. Waring (Department of\nPathology, University of Melbourne, Parkville, Victoria, Australia), V.\nBillson (The Royal Women ’s Hospital, Parkville, Victoria, Australia),\nJ. Pyman (The Royal Women ’s Hospital, Parkville, Victoria, Australia),\nD. Neesham (The Royal Women ’s Hospital, Parkville, Victoria, Aus-\ntralia), M. Quinn (The Royal Women ’s Hospital, Parkville, Victoria,\nAustralia), C. Underhill (Border Medical Oncology, Wodonga, Victoria,\nAustralia), R. Bell (Andrew Love Cancer Centre, Geelong, Victoria,\nAustralia), LF Ng (Ballarat Base Hospital, Ballarat, Victoria, Australia),\nR. Blum (Bendigo Health Care Group, Bendigo, Victoria, Australia), V.\nGanju (Peninsula Health, Frankston, Victoria, Australia), I. Hammond\n(Women and Infant ’s Research Foundation, King Edward Memorial\nHospital, Subiaco, Western Australia, Australia), Y. Leung (Women and\nInfant’s Research Foundation, King Edward Memorial Hospital,\nSubiaco, Western Australia, Australia), A. McCartney (Women and\nInfant’s Research Foundation, King Edward Memorial Hospital,\nSubiaco, Western Australia, Australia) (dec), M. Buck (Mount Hospital,\nPerth, Western Australia, Australia), I. Haviv (Faculty of Medicine,\nBar-Ilan University, Safed, Israel), D. Purdie (QIMR Berghofer Medical\nResearch Institute, Brisbane, Queensland, Australia), D. Whiteman\n(QIMR Berghofer Medical Research Institute, Brisbane, Queensland,\nAustralia), N. Zeps (Western Australian Research Tissue Network\n(WARTN), St John of God Pathology, Osborne Park, Western Australia,\nAustralia)\nPublished by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\n  AUS\n  DOV\n  HAW\n  HOP\n  NCO\n  UCI\n  UKO\n  USC\n  AARP\n  CPS2\n  CTS\n  IWHS\n  NHS\n  NHSII\n  PLCO\n  SISTERS\n  VITAL\nCase-control\nCohort\nOverall\nHeterogeneity: /g87\n2 = 0.02, I2 = 42.84%, H2 = 1.75\nHeterogeneity: /g872 = 0.00, I2 = 0.00%, H2 = 1.00\nHeterogeneity: /g872 = 0.00, I2 = 10.66%, H2 = 1.12\nTest of /g84i = /g84j: Q(7) = 12.21, P = .09\nTest of /g84i = /g84j: Q(8) = 4.02, P = .85\nTest of /g84i = /g84j: Q(16) = 17.28, P = .37\nTest of group differences: Qb(1) = 0.51, P = .47\nStudy\n1/4 1/2 1 2 4\nRR (95% CI)\n0.98 (0.71 to 1.35) \n0.80 (0.64 to 1.00)\n0.74 (0.47 to 1.15)\n0.73 (0.59 to 0.91)\n0.57 (0.38 to 0.84)\n0.91 (0.62 to 1.35)\n0.93 (0.61 to 1.40)\n1.27 (0.89 to 1.80)\n0.94 (0.76 to 1.16)\n0.81 (0.60 to 1.10)\n1.24 (0.77 to 1.99)\n0.92 (0.65 to 1.30)\n0.99 (0.73 to 1.34)\n0.85 (0.45 to 1.61)\n0.77 (0.59 to 1.02)\n0.93 (0.39 to 2.23)\n0.85 (0.54 to 1.32)\n0.84 (0.72 to 0.98)\n0.90 (0.81 to 1.01)\n0.87 (0.80 to 0.94)\n6.26\n11.14\n3.42\n11.91\n4.28\n4.42\n3.90\n5.35\n12.70\n7.02\n3.02\n5.37\n6.95\n1.76\n8.12\n0.92\n3.47\nWeight\n(%)\nRandom-effects REML model\nFIG A1. Meta-analysis of the overall association a between frequent aspirin use and ovarian cancer risk in OC3\nand OCAC. aAdjusted for age, parity, duration of oral contraceptive use, duration of menopausal hormone therapy\nuse, and BMI. AARP, NIH-AARP Diet and Health Study; AUS, Australian Ovarian Cancer Study & Australian\nCancer Study; BMI, body mass index; CPS2, Cancer Prevention Study II Nutrition Cohort; CTS, California\nTeachers Study, DOV, Diseases of the Ovary and their Evaluation Study; HAW, Hawaii Ovarian Cancer Study;\nHOP, Hormones and Ovarian Cancer Prediction Study; IWHS, Iowa Women's Health Study; NCO, North Carolina\nOvarian Cancer Study; NHS, Nurses' Health Study; NHSII, Nurses' Health Study II; OC3, Ovarian Cancer Cohort\nConsortium; OCAC, Ovarian Cancer Association Consortium; PLCO, Prostate, Lung, Colorectal, and Ovarian\nCancer Screening Trial; RR, relative risk; SISTERS, Sister Study; UCI, University of California, Irvine Ovarian\nCancer Study; UKO, United Kingdom Ovarian Cancer Population Study; USC, University of Southern California,\nStudy of Lifestyle and Women ’s Health; VITAL, Vitamins and Lifestyle Cohort.\nJournal of Clinical Oncology\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nTABLE A1. Characteristics of the Included Cohort Studies From Ovarian Cancer Cohort Consortium\nStudy Acronym Location\nBaseline\nEnrollment Perioda\nQuestionnaire Item for\nAspirin Use\nCategories for\nFrequency of Use\nNo. at\nRisk\nNo. of\nEvents\nAverage\nFollow-Up,a\nyears (max)\nAverage Age at\nEntry,b years\nPrevalence of\nFrequent Aspirin Use\nNIH-AARP Diet and\nHealth Study\nAARP United\nStates\n1995-1996 During the past 12\nmonths, did you take\nany of the following\naspirin products?\n, 2/month, 2-3/\nmonth, 1-2/week,\n3-4/week, 5-6/\nweek, 1/day,\n$ 2/day\n98,367 649 9.8 (11.2) 61.9 19.9%\nCancer Prevention\nStudy II Nutrition\nCohort\nCPS2 United\nStates\n1992-1993 During the past year, did\nyou take any of the\nfollowing medications\nregularly?\nFill in times per\nmonth, pills per\nday\n63,380 538 13.8 (16.7) 62.0 14.3%\nCalifornia Teachers\nStudy\nCTS United\nStates\n1995 Have you taken any of the\nfollowing medications\nregularly (at least once\na week)? If so, indicate\nhow many total years\nyou took it and how\noften you took it\n1-3, 4-6, every day 43,782 185 14.3 (15.2) 51.8 9.8%\nIowa Women’s Health\nStudy\nIWHS United\nStates\n1986 On average, how often do\nyou take aspirin?\nNever, , 1/week,\n1/week, 2-5/week,\n6-7/week, 8-14/\nweek, 15 1/week\n23,269 222 14.0 (16.2) 68.2 38.0%\nNurses’ Health Study NHS United\nStates\n1976 Mark if used regularly in\nthe past 2 years\nDays/week: 1, 2-3,\n4-5, 6 1; Tablets/\nweek: 1-2, 3-5,\n6-14, 15 1 tablets\n58,357 339 9.2 (10.0) 65.8 35.8%\nNurses’ Health\nStudy II\nNHSII United\nStates\n1989 Mark if used regularly in\nthe past 2 years\nDays/week: 1, 2-3,\n4-5, 6 1; Tablets/\nweek: 1-2, 3-5,\n6-14, 15 1 tablets\n77,235 137 9.7 (10.0) 46.0 10.9%\nProstate, Lung,\nColorectal, and\nOvarian Cancer\nScreening Trial\nPLCO United\nStates\n1993-2002 During the past 12\nmonths, have you\nregularly used aspirin or\naspirin-containing\nproducts?\n1/day, 2 1/day,\n1/week, 2/week,\n3-4/week, ,\n2/month, 2-3/\nmonth\n60,144 363 11.9 (17.0) 62.5 29.3%\nSister Study SISTERS United\nStates\n2003-2009 Do you currently take any\nprescription or\nnonprescription\nmedications at least\nonce a week? Also\ncaptured information in\na grid-format to\nascertain lifetime\nmedication usage\nFill in days per week,\ntimes per day\n39,195 39 4.6 (8.1) 54.7 20.6%\n(continued on following page)\nPublished by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nTABLE A1. Characteristics of the Included Cohort Studies From Ovarian Cancer Cohort Consortium (continued)\nStudy Acronym Location\nBaseline\nEnrollment Perioda\nQuestionnaire Item for\nAspirin Use\nCategories for\nFrequency of Use\nNo. at\nRisk\nNo. of\nEvents\nAverage\nFollow-Up,a\nyears (max)\nAverage Age at\nEntry,b years\nPrevalence of\nFrequent Aspirin Use\nVitamins and Lifestyle\nCohort\nVITAL United\nStates\n2000-2002 In the past 10 years, did\nyou take any of the\nfollowing medications\nat least one per week for\na year?\n1-3, 4-6, 7\ndays/week\n27,922 128 9.4 (11.2) 61.3 25.5%\naFollow-up time for this analysis began accruing at the time of the questionnaire collecting information on frequency of aspirin use (AARP: 1996-1997 ; IWHS: 1992; NHS: 2000-2001; NHSII:\n2001-2002).\nbAge at the time of the questionnaire collecting information on frequency of aspirin use.\nJournal of Clinical Oncology\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nTABLE A2. Characteristics of the Included Case-Control Studies From Ovarian Cancer Association Consortium\nStudy Acronym Location\nAscertainment\nPeriod Cases Controls\nQuestionnaire Item for\nAspirin Use\nCategories for\nFrequency of Use\nAverage Age at Entry\nfor Cases, years\nPrevalence of\nFrequent Aspirin Use\nAmong Controls (%)\nAustralian Ovarian\nCancer Study &\nAustralian Cancer\nStudy\nAUS Australia 2002-2006 1,311 1,505 How often have you taken\nthe following\nover-the-counter\n(aspirin, paracetamol,\nanti-inflammatory\ndrugs) medications\nduring the PAST 5\nyears?\nNever, occasionally,\n, 1/month, 1/week,\n2-3/week, 4-7/\nweek, 2 1/day\n59.3 6.2\nDiseases of the Ovary\nand their\nEvaluation Study\nDOV United\nStates\n2002-2009 1,159 1,849 Before the reference\ndate, have you taken\nany of these\nmedications (show\ncard) 5 or more days\nper month for at least 6\nmonths?\nDays per month: 5-7,\n8-14, . 14 days but\nless than daily, daily,\nor almost daily\n56.2 14.9\nHawaii Ovarian\nCancer Study\nHAW United\nStates\n2001-2008 256 485 Did you ever take an\naspirin product (show\ncard) at least 12 times\na year?\nNo. of pills taken per\nday, week, or month\n56.9 19.2\nHormones and\nOvarian Cancer\nPrediction Study\nHOP United\nStates\n2003-2008 683 1,513 Before reference date\nhave you ever used\naspirin (show card) for\nat least two tablets per\nweek continuously for a\nperiod of 6 months or\nlonger?\nNo. of pills taken per\nday, week, or month\n60.2 29.8\nNorth Carolina\nOvarian Cancer\nStudy\nNCO United\nStates\n1999-2008 939 1,085 For the 5 years before\ndiagnosis, did you take\nany of these\nover-the-counter\nmedications (show\ncard) on a regular basis\nfor at least 3 months?\nDays per month: # 1,\n2-7, 8-14, . 14,\ndaily or almost daily\n57.2 9.0\n(continued on following page)\nPublished by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nTABLE A2. Characteristics of the Included Case-Control Studies From Ovarian Cancer Association Consortium (continued)\nStudy Acronym Location\nAscertainment\nPeriod Cases Controls\nQuestionnaire Item for\nAspirin Use\nCategories for\nFrequency of Use\nAverage Age at Entry\nfor Cases, years\nPrevalence of\nFrequent Aspirin Use\nAmong Controls (%)\nUniversity of\nCalifornia, Irvine\nOvarian Cancer\nStudy\nUCI United\nStates\n1995-2005 393 313 Have you taken\nmedication listed\n(aspirin, ibuprofen,\nacetaminophen, and\nnaproxen) regularly?\nBy regular, we are\nreferring to use of the\ndrug or medication at\nleast once a week for a\nyear, or more than 50\npills during a one\nyear-period\nNo. of pills/week 58.0 5.6\nUnited Kingdom\nOvarian Cancer\nPopulation Study\nUKO United\nKingdom\n2006-2007 516 598 Have you ever used any\nmedication containing\nthe drugs (aspirin or\nibuprofen) on a regular\nbasis (by regular, we\nmean every day or\nalmost every day for 6\nmonths or longer)?\nEvery day or almost\nevery day\n60.7 15.2\nUniversity of\nSouthern\nCalifornia, Study of\nLifestyle and\nWomen’s Health\nUSC United\nStates\n2000-2005 469 679 Before reference date, as\nan adult, did you ever\ntake any prescription or\nnonprescription\nmedicine at least 2 or\nmore times per week\nfor one month or\nlonger?\nNo. of days/month 57.0 12.7\nJournal of Clinical Oncology\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nTABLE A3. Summary RRs and 95% CIs for the Associations Between Frequent Aspirin Use and Each Ovarian Cancer Histotype in OC3 and OCAC, Overall\nand by Key Subgroups of Interest\nSubgroup\nHigh-Grade Serous, RR\n(95% CI)\nEndometrioid, RR\n(95% CI)\nClear Cell, RR\n(95% CI)\nMucinous, RR\n(95% CI)\nOther/Unknown\nEpithelial, RR (95% CI) P-Heterogeneity\nOverall 0.86 (0.78 to 0.94) 0.80 (0.67 to 0.96) 0.93 (0.71 to 1.22) 1.00 (0.73 to 1.36) 0.94 (0.81 to 1.10) .60\nEndometriosis\nNo 0.80 (0.72 to 0.88) 0.76 (0.62 to 0.93) 0.91 (0.68 to 1.23) 1.17 (0.82 to 1.67) 0.91 (0.76 to 1.09) .17\nYes 1.30 (0.78 to 2.16) 0.78 (0.45 to 1.36) 0.97 (0.50 to 1.85) 0.59 (0.24 to 1.43) 1.84 (0.71 to 4.78) .31\nObesity\nNo 0.87 (0.78 to 0.98) 0.79 (0.64 to 0.99) 0.71 (0.55 to 0.93) 1.23 (0.85 to 1.77) 0.95 (0.79 to 1.14) .13\nYes 0.79 (0.66 to 0.96) 0.69 (0.51 to 0.93) 0.99 (0.57 to 1.74) 0.89 (0.44 to 1.81) 0.90 (0.67 to 1.22) .69\nFamily history of\nbreast/\novarian\ncancer\nNo 0.85 (0.77 to 0.94) 0.82 (0.67 to 1.00) 0.87 (0.65 to 1.17) 0.91 (0.67 to 1.22) 0.91 (0.77 to 1.08) .93\nYes 0.82 (0.66 to 1.01) 0.76 (0.52 to 1.12) 1.12 (0.64 to 1.98) 1.26 (0.36 to 4.41) 1.01 (0.69 to 1.47) .64\nNulliparity\nNo 0.85 (0.77 to 0.94) 0.82 (0.66 to 1.01) 0.99 (0.71 to 1.37) 1.03 (0.73 to 1.45) 0.99 (0.84 to 1.17) .39\nYes 0.84 (0.67 to 1.05) 0.72 (0.52 to 1.00) 0.67 (0.46 to 0.98) 1.01 (0.53 to 1.91) 0.68 (0.49 to 0.94) .64\nDuration of OC\nuse, years\nNever 0.80 (0.70 to 0.91) 0.72 (0.56 to 0.93) 1.11 (0.71 to 1.71) 1.18 (0.77 to 1.82) 0.88 (0.71 to 1.09) .19\n, 5 0.88 (0.74 to 1.05) 0.79 (0.57 to 1.09) 0.79 (0.52 to 1.20) 0.60 (0.37 to 0.97) 0.89 (0.70 to 1.15) .62\n$ 5 0.87 (0.72 to 1.05) 0.96 (0.65 to 1.41) 0.58 (0.38 to 0.89) 1.07 (0.53 to 2.19) 1.10 (0.71 to 1.69) .27\nTubal ligation\nNo 0.83 (0.75 to 0.93) 0.82 (0.66 to 1.01) 0.85 (0.65 to 1.12) 1.15 (0.80 to 1.65) 0.97 (0.80 to 1.17) .35\nYes 0.86 (0.69 to 1.07) 0.71 (0.47 to 1.06) 1.00 (0.47 to 2.15) 0.65 (0.33 to 1.29) 0.97 (0.67 to 1.40) .74\nOvarian cancer\nrisk score\n0 0.97 (0.69 to 1.38) 0.95 (0.32 to 2.84) 1.22 (0.41 to 3.65) 1.11 (0.66 to 1.85) .96\n1 1.00 (0.84 to 1.19) 1.02 (0.68 to 1.52) 1.08 (0.62 to 1.88) 0.64 (0.31 to 1.32) 1.06 (0.80 to 1.39) .79\n21 0.83 (0.73 to 0.95) 0.67 (0.51 to 0.86) 0.79 (0.58 to 1.09) 0.93 (0.63 to 1.35) 0.91 (0.74 to 1.12) .42\nNOTE. Models were adjusted for age, parity, duration of oral contraceptive use, duration of menopausal hormone therapy use, BMI, and study. Models\nstratified by risk score were adjusted for age, duration of menopausal hormone therapy use, and study. For mucinous ovarian cancers, the relative risk for\nwomen with ovarian cancer risk score 5 0 was unable to be estimated.\nAbbreviations: BMI, body mass index; OC, oral contraceptive; OC3, Ovarian Cancer Cohort Consortium; OCAC, Ovarian Cancer Association Consortium;\nRR, relative risk.\nPublished by American Society of Clinical Oncology\nHurwitz et al\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved. \n\nTABLE A4. NNT With Frequent Aspirin Use to Prevent One Incident Ovarian Cancer Within 10 Years, Overall and by the Ovarian Cancer Risk Score\nSubgroup\nNo. of Cases From\nCohort Studies\nNo. of Cases From\nCase-Control Studies\n10-Year Cumulative\nIncidence of Ovarian\nCancer in Nonaspirin\nUsersa RR (95% CI) b NNT (95% CI) c\nOverall 2,600 5,726 0.00432 0.87 (0.80 to 0.94) 1,784 (1,160 to 3,866)\nOvarian cancer\nrisk score\n0 447 438 0.00343 0.97 (0.79 to 1.19) 9,735 (1,391 to ‘)d\n1 943 1,377 0.00481 0.93 (0.82 to 1.06) 2,977 (1,158 to ‘)d\n21 1,151 3,104 0.00544 0.81 (0.73 to 0.90) 970 (683 to 1,843)\nAbbreviations: NNH, number needed to harm; NNT, number needed to treat; RR, relative risk.\naCalculated using the pooled cohort study data.\nbCombined cohort and case-control summary RRs for the association between frequent aspirin use and ovarian cancer risk.\ncNNT 5 1/(S(t)RR – S(t)), where S(t) 5 1- to 10-year cumulative incidence of ovarian cancer in nonaspirin users. 54\ndGiven that the 95% CI for the RR overlaps 1, we cannot preclude the possibility that frequent aspirin use is associated with harm (ie, the full 95% CI extends\nto include the possibility of a positive NNH). 60\nJournal of Clinical Oncology\nAspirin Use and Ovarian Cancer Risk Among Subgroups of Interest\nDownloaded from ascopubs.org by UCL Library Services on July 27, 2022 from 128.040.216.035\nCopyright © 2022 American Society of Clinical Oncology. All rights reserved.","source_license":"CC0","license_restricted":false}