Reproductive Factors Do Not Influence Survival with Ovarian Cancer

Invasive epithelial ovarian cancer (ovarian cancer) has a 5-year survival rate of less than 50%. Cigarette smoking (1) and higher body mass index (2) before diagnosis are both associated with poor survival, whereas menopausal hormone therapy use is a positive prognostic indicator (3). However, the literature surrounding the association between reproductive factors and ovarian cancer survival is equivocal even though many are associated with risk of the disease. Older age at menarche has been associated with both poor (4) and longer survival (5), but three other studies have found no relationship (6–8). Similarly, some (6, 7), but not all (4, 5, 8) studies have reported that parity is associated with better survival. One study reported a decreased death rate among those who used combined oral contraceptives (COC; ref. 8), but most studies did not observe an association (4–6). A major concern with these studies is power; to our knowledge, the largest published study of reproductive factors and ovarian cancer survival included 1,698 patients (4). Therefore, we have used data from 11,175 patients with ovarian cancer in the Ovarian Cancer Association Consortium (OCAC) to clarify the associations between survival and age at menarche, COC use, parity, breastfeeding, age at last pregnancy, and menopausal status.

This analysis used self-reported data from 16 studies in the OCAC, including two studies from Australia, four from Europe, and ten from the United States (US; http://ocac.ccge.medschl.cam.ac.uk/; Table 1). All studies obtained institutional ethics committee approval and followed recognized ethnical guidelines, including the Declaration of Helsinki, the Belmont Report, and/or the US Common Rule; and participants provided written informed consent. Participants who were diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal tumors (hereafter referred to as ovarian cancer) were included in the analysis. To be included, patients had to have been diagnosed with one of the five main histotypes (i.e., high-grade serous, endometrioid, clear cell, mucinous, and low-grade serous) and had follow-up time and vital status information available. Survival time was counted from date of diagnosis to either death or last follow-up. Follow-up is largely done via linkage with national death databases.

The six prediagnosis reproductive factors of interest were age at menarche, COC use, parity, breastfeeding, age at last pregnancy, and menopausal status. The covariates included age at diagnosis, race/ethnicity, education level, stage, histotype, and OCAC study. The percentage of patients missing data on any variables ranged from none for age to 5.9% for education level. Multiple imputations (mice package in R) were conducted to create 20 imputed datasets. All variables in the dataset with ≤70% missingness were included for imputation, including the six reproductive factors and those not used in the final models. Data were imputed separately by geographic region (i.e., Australia, Europe, and US), and OCAC study was included as a predictor in all imputation models.

Cox proportional hazards models were fit for all-cause mortality among patients with ovarian cancer overall and by histotype. All models included the six reproductive factors of interest (see above); were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study; and stratified on stage and histotype (see Table 2 for the coding schemes). Hazard ratios (HR) and 95% confidence intervals (CI) across the 20 imputed datasets were pooled using Rubin's rule to obtain a single point estimate and pooled standard error for each reproductive factor. The pooled standard error is derived from within and between imputation variances. Adjusting for cigarette smoking, menopausal hormone therapy, body mass index, and aspirin use did not change the results. Including only patients with complete information (N = 9,422) yielded similar results. No evidence of heterogeneity between the OCAC studies for each factor–survival association was found using standard meta-analytic techniques.

The data generated in this study are not publicly available due to limitations imposed by the original studies in which these data were collected. The corresponding author will facilitate access through existing data request processes for the OCAC.

Of the 11,175 patients with ovarian cancer included in the analysis, there were 6,418 deaths (57.4%) during an average follow-up of 6.34 years (SD = 4.80; Table 1). There were no statistically significant reproductive factor–survival associations among patients with ovarian cancer overall or by histotype (Table 2). There were two borderline significant associations with survival: breastfeeding for 24+ months (HR, 1.11; 95% CI, 0.99–1.24) and age at last pregnancy 30 to 34 years (HR, 0.92; 95% CI, 0.85–1.00, Table 2). However, there were no trends across the categories of these exposures suggesting that the associations were likely due to chance. Similarly, there were several borderline significant associations within each histotype, but they were likely due to chance for the same reasons (Table 2).

Our study was the largest to date to investigate reproductive factors and survival among patients with ovarian cancer, and found no statistically significant associations. Our sample size of more than 11,000 patients afforded us sufficient statistical power to detect potential associations. It further enabled histotype-specific analyses, which had not been evaluated previously. Our cohort's 6-year survival of 43% is close to the Surveillance, Epidemiology, and End Results Program 5-year survival of 47%, suggesting that our cohort is well-representative of patients with ovarian cancer. However, due to a large proportion of missing data for debulking status, treatment, and time to recurrence, we could not consider these factors in the analysis. Overall, our findings highlight that the prediagnosis reproductive factors included in this analysis have no significant impact on ovarian cancer survival regardless of their effects on the risk of developing ovarian cancer.

J.M. Schildkraut reports grants from NIH/NCI during the conduct of the study. E.V. Bandera reports Serving in a Pfizer Advisory Board to Enhance Diversity in Clinical Trials. U. Menon reports grants from Cancer Research UK (CRUK), The Eve Appeal, grants from NIHR HTA, UCL GCRF Internal Small Grant, MRC Proximity to Discovery Industrial Connectivity Award, grants from NIHR BRC UCLH, other support from Abcodia Ltd., British Council, and personal fees from New York Obs. and Gyne. Society, outside the submitted work; in addition, and reports a patent for Patent no: EP10178345.4 issued. F. Modugno reports grants from National Cancer Institute and Department of Defense during the conduct of the study. P.D.P. Pharoah reports grants from Cancer Research UK during the conduct of the study. H.A. Risch reports grants from NIH during the conduct of the study. P.M. Webb reports grants from U.S. Army Medical Research and Materiel Command and National Health and Medical Research Council of Australia during the conduct of the study; grants from AstraZeneca outside the submitted work. C.L. Pearce reports grants from DoD and NIH during the conduct of the study. No disclosures were reported by the other authors.

M.T. Phung: Formal analysis, methodology, writing–original draft. A. Alimujiang: Formal analysis, writing–original draft, writing–review and editing. A. Berchuck: Writing–review and editing. H. Anton-Cluver: Funding acquisition, writing–review and editing. J.M. Schildkraut: Funding acquisition, writing–review and editing. E.V. Bandera: Data curation, funding acquisition, writing–review and editing. J. Chang-Claude: Funding acquisition, writing–review and editing. A. Chase: Writing–review and editing. J.A. Doherty: Funding acquisition, writing–review and editing. B. Grout: Writing–review and editing. M.T. Goodman: Funding acquisition, writing–review and editing. G.E. Hanley: Funding acquisition, methodology, writing–review and editing. A.W. Lee: Conceptualization, data curation, formal analysis, writing–review and editing. C. McKinnon Deurloo: Writing–review and editing. U. Menon: Funding acquisition, writing–review and editing. F. Modugno: Funding acquisition, writing–review and editing. P.D.P. Pharoah: Funding acquisition, writing–review and editing. M.C. Pike: Conceptualization, funding acquisition, methodology, writing–review and editing. J. Richardson: Writing–review and editing. H.A. Risch: Funding acquisition, writing–review and editing. W. Sieh: Funding acquisition, writing–review and editing. K.L. Terry: Funding acquisition, writing–review and editing. P.M. Webb: Conceptualization, funding acquisition, methodology, writing–review and editing. N. Wentzensen: Writing–review and editing. A.H. Wu: Funding acquisition, writing–review and editing. C.L. Pearce: Conceptualization, data curation, formal analysis, supervision, funding acquisition, investigation, methodology, writing–original draft.

We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. We thank the study participants, doctors, nurses, clinical and scientific collaborators, health care providers, and health information sources who have contributed to the studies contributing to this article. Acknowledgements for individual studies: AUS: The AOCS also acknowledges the cooperation of the participating institutions in Australia, and the contribution of the study nurses, research assistants and all clinical and scientific collaborators. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in this research program; CON: The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data; GER: The German Ovarian Cancer Study thank Ursula Eilber for competent technical assistance; OPL: Members of the OPAL Study Group (http://opalstudy.qimrberghofer.edu.au/); SEA: SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy; UKO: We particularly thank I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. NJO: Drs. S. Olson, L. Paddock, and L. Rodriguez, and research staff at the Rutgers Cancer Institute of New Jersey, Memorial Sloan-Kettering Cancer Center, and the New Jersey State Cancer Registry. OCAC Funding: The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07 to A. Berchuck). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112; to C.L. Pearce and J.M. Schildkraut). Funding for individual studies: AUS: The Australian Ovarian Cancer Study (AOCS) was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729; to P.M. Webb), National Health & Medical Research Council of Australia (199600, 400413 and 400281; to P.M. Webb), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211, and 182; to P.M. Webb). AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; P.M. Webb is supported by NHMRC Investigator Grant APP1173346; OPL: National Health and Medical Research Council (NHMRC) of Australia (APP1025142, APP1120431 to P.M. Webb) and Brisbane Women's Club (to P.M. Webb); GER: German Federal Ministry of Education and Research, Program of Clinical Biomedical Research (01 GB 9401; to J. Chang-Claude), and the German Cancer Research Center (DKFZ, to J. Chang-Claude); POL: Intramural Research Program of the National Cancer Institute (to N. Wentzensen); SEA: The SEARCH study was supported by Cancer Research UK (C490/A8339, C490/A10119, C490/A10124, and C490/A16561; to P.D.P. Pharoah) and UK National Institute for Health Research Biomedical Research Center at the University of Cambridge (to P.D.P. Pharoah); UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation; to U. Menon) with investigators supported by the National Institute for Health Research University College London Hospitals Biomedical Research Center and (MR_UU_12023; to U. Menon); STA: NIH grants U01 CA71966 and U01 CA69417 (to W. Sieh); CON: National Institutes of Health (R01-CA063678, R01-CA074850; R01-CA080742; to H.A. Risch); DOV: National Institutes of Health R01-CA112523 and R01-CA87538 (to J.A. Doherty); HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001; to M.T. Goodman); HOP: Department of Defense (DAMD17-02-1-0669; to F. Modugno) and NCI (K07-CA080668, R01-CA95023, P50-CA159981, MO1-RR000056, R01-CA126841; to F. Modugno); NCO: National Institutes of Health (R01-CA76016; to A. Berchuck and J.M. Schildkraut) and the Department of Defense (DAMD17-02-1-0666 to A. Berchuck); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802 (to K.L. Terry); NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720; to E.V. Bandera) and the Rutgers Cancer Institute of New Jersey (to E.V. Bandera); UCI: NIH (R01-CA058860; to H. Anton-Culver) and the Lon V Smith Foundation (grant LVS-39420; to H. Anton-Culver); USC: National Institutes of Health (P01CA17054, N01PC67010, N01CN025403; to A.H. Wu, M.C. Pike, and C.L. Pearce; P30CA14089; to A.H. Wu and M.C. Pike; R01CA61132 to M.C. Pike; R03CA113148 and R03CA115195; to C.L. Pearce); and California Cancer Research Program (00-01389V-20170; to M.C. Pike and C.L. Pearce; 2II0200; to A.H. Wu); Dr. Pike is partially supported by the NIH/NCI support grant P30 CA008748 to Memorial Sloan Kettering Cancer Center.

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