Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

Lieske H. Schrijver, Antonis C. Antoniou, Epidemiological Study of Familial Breast Cancer, Gene Etude Prospective Sein Ovaire Sein, Hereditary Breast and Ovarian Cancer Research Group Netherlands, and International BRCA1/2 Carrier Cohort Study, Håkan Olsson, Thea M. Mooij, Marie José Roos-Blom, Leyla Azarang, Julian Adlard, Munaza Ahmed, Daniel Barrowdale, Rosemarie Davidson, Alan Donaldson, Ros Eeles, D. Gareth Evans, Debra Frost, Alex Henderson, Louise Izatt, Kai Ren Ong, Valérie Bonadona, Isabelle CoupierLaurence Faivre, Jean Pierre Fricker, Paul Gesta, Klaartje van Engelen, Agnes Jager, Fred H. Menko, Marian J.E. Mourits, Christian F. Singer, Yen Y. Tan, Lenka Foretova, Marie Navratilova, Rita K. Schmutzler, Carolina Ellberg, Christoph Engel, N Andrieu, Matti A. Rookus

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Abstract

Background: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. Objective: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. Study Design: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent–weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. Results: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5–9 years [hazard ratio, 0.67; 95% confidence interval, 0.40–1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19–0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14–0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18–0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. Conclusion: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

Original languageEnglish
Pages (from-to)51.e1-51.e17
JournalAmerican Journal of Obstetrics and Gynecology
Volume225
Issue number1
DOIs
Publication statusPublished - 1 Jul 2021

Bibliographical note

Funding Information:
The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and by grants from the Ligue Nationale Contre le Cancer and is being supported by a grant from Institute National du Cancer as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, n2014-008).

Funding Information:
Part of this work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program (grant number CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant number PSR-SIIRI-701). The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation .

Funding Information:
The International Hereditary Cancer Centre was supported by grant number PBZ_KBN_122/P05/2004 and by the National Center for Research and Development (NCBR) within the framework of the international ERA-NET TRANSAN JTC 2012 application number Cancer 12-054 (contract number ERA-NET-TRANSCAN/07/2014).

Funding Information:
The Health Care Service Corporation was supported by a grant RD12/0036/0006 and 15/00059 from Instituto de Salud Carlos III (Spain), partially supported by European Regional Development FEDER funds.

Funding Information:
This work was supported by Cancer Research UK grants C12292/A20861 and C12292/A11174.

Funding Information:
EMBRACE is supported by Cancer Research UK grants C1287/A10118 and C1287/A11990. D.G.E. is supported by a National Institute for Health Research (NIHR) grant through the Biomedical Research Centre , Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant through the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.E. and E.B. are supported by a Cancer Research UK grant C5047/A8385. R.E. is also supported by the NIHR through the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. A.C.A. is funded by Cancer Research UK grants C12292/A20861, C12292/A11174.

Funding Information:
This work was partially supported by the Spanish Ministry of Economy and Competitiveness (SAF2014-57680-R) and the Spanish Centre for Biomedical Network Research on Rare Diseases. This work was partially supported by Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX grant number FISPI05/2275 and by the Mutua Madrileña Foundation (FMMA).

Funding Information:
The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, and NKI2007-3756; the Netherlands Organisation of Scientific Research grant NWO 91109024; the Pink Ribbon grants 110005 and 2014-187.WO76; the Biobanking and BioMolecular Resources Research Infrastructure grant NWO 184.021.007/CP46; and the TRANSCAN grant JTC 2012 Cancer 12-054.

Funding Information:
This study was supported by the German Cancer Research Center .

Funding Information:
This work was supported by Cancer Research UK grants C12292/A20861 and C12292/A11174.This work was partially supported by the Spanish Ministry of Economy and Competitiveness (SAF2014-57680-R) and the Spanish Centre for Biomedical Network Research on Rare Diseases. This work was partially supported by Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX grant number FISPI05/2275 and by the Mutua Madrile?a Foundation (FMMA).Part of this work was supported by the Canadian Institutes of Health Research for the ?CIHR Team in Familial Risks of Breast Cancer? program (grant number CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant number PSR-SIIRI-701). The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Minist?re de l??conomie, de la Science et de l'Innovation du Qu?bec through Genome Qu?bec, and the Quebec Breast Cancer Foundation.This study was supported by the German Cancer Research Center.EMBRACE is supported by Cancer Research UK grants C1287/A10118 and C1287/A11990. D.G.E. is supported by a National Institute for Health Research (NIHR) grant through the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant through the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.E. and E.B. are supported by a Cancer Research UK grant C5047/A8385. R.E. is also supported by the NIHR through the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. A.C.A. is funded by Cancer Research UK grants C12292/A20861, C12292/A11174.The German Consortium of Hereditary Breast and Ovarian Cancer is supported by the German Cancer Aid (grant number 110837; R.K.S.). This work was supported by LIFE ? Leipzig Research Center for Civilization Diseases, Universit?t Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund, and by means of the Free State of Saxony within the framework of the excellence initiative.The Health Care Service Corporation was supported by a grant RD12/0036/0006 and 15/00059 from Instituto de Salud Carlos III (Spain), partially supported by European Regional Development FEDER funds.The International Hereditary Cancer Centre was supported by grant number PBZ_KBN_122/P05/2004 and by the National Center for Research and Development (NCBR) within the framework of the international ERA-NET TRANSAN JTC 2012 application number Cancer 12-054 (contract number ERA-NET-TRANSCAN/07/2014).Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council advanced grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and by grants from the Ligue Nationale Contre le Cancer and is being supported by a grant from Institute National du Cancer as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, n2014-008). The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, and NKI2007-3756; the Netherlands Organisation of Scientific Research grant NWO 91109024; the Pink Ribbon grants 110005 and 2014-187.WO76; the Biobanking and BioMolecular Resources Research Infrastructure grant NWO 184.021.007/CP46; and the TRANSCAN grant JTC 2012 Cancer 12-054. MODSQUAD ? Czech Republic, Brno, was supported by MH CZ ? DRO (MMCI, 00209805). The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian research grants KTIA-OTKA CK-80745 and NKFI OTKA K-112228 and by the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/?P-9.

Funding Information:
The German Consortium of Hereditary Breast and Ovarian Cancer is supported by the German Cancer Aid (grant number 110837; R.K.S.). This work was supported by LIFE – Leipzig Research Center for Civilization Diseases, Universität Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund, and by means of the Free State of Saxony within the framework of the excellence initiative.

Publisher Copyright:
© 2021 The Authors

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