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.

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Melbourne Victoria Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Melbourne Victoria Australia; Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Melbourne Victoria Australia; Department of Oncology Peter MacCallum Cancer Centre University of Melbourne Parkville Australia; Department of Medical Oncology Peter MacCallum Cancer Centre Victoria Australia

Centre for Life Institute of Genetic Medicine Newcastle upon Tyne Hospitals NHS Trust Newcastle upon Tyne United Kingdom

Centre Hospitalier Universitaire de Montpellier Hôpital Arnaud de Villeneuve Montpellier France; Service de Génétique médicale et Oncogénétique Montpellier France; Institut National de la Santé et de la Recherche Médicale Centre de Recherche en Cancérologie de Marseille Val d'Aurel Montpellier France

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London United Kingdom

Département d'Anticipation et de Suivi des Cancers Oncogénétique Clinique Institut Paoli Calmettes Marseille France; Institut National de la Santé et de la Recherche Médicale Institut de Recherche pour le Développement Sciences Economiques and Sociales de la Santé and Traitement de l'Information Médicale Aix Marseille University Marseille France

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Genetics Amsterdam University Medical Center Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Rigshospitalet København Denmark

Department of Clinical Genetics South Glasgow University Hospitals Glasgow United Kingdom

Department of Clinical Genetics St Michael's Hospital Bristol United Kingdom

Department of Dermatology University of Utah School of Medicine Salt Lake City UT

Department of Epidemiology Mailman School of Public Health Columbia University New York NY

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin Poland

Department of Gynaecology University Medical Center Groningen University of Groningen Groningen the Netherlands

Department of Gynecology and Obstetrics Medical Faculty and University Hospital Carl Gustav Carus Technische Universität Dresden Germany

Department of Medical Oncology Family Cancer Clinic Erasmus Medical Center Cancer Institute Rotterdam the Netherlands

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Obstetrics and Gynecology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Oncology Lund University Hospital Lund Sweden

Division of Evolution and Genomic Sciences Department of Genomic Medicine Manchester Academic Health Sciences Centre Manchester University Manchester University Hospitals NHS Foundation Trust Manchester United Kingdom

Division of Oncology and Pathology Department of Clinical Sciences Lund Lund University Lund Sweden

Family Cancer Clinic Netherlands Cancer Institute Amsterdam the Netherlands

Genomic and Immunotherapy Medical Institute Hôpital d'Enfants Centre Hospitalier Universitaire de Dijon Dijon France; Unité d'Oncogénétique Centre de Lutte Contre le Cancer Georges François Leclerc Dijon France

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center Québec City Québec Canada

Human Genetics Group Centro Nacional De Investigaciones Oncologicas Madrid Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid Spain

Institut National de la Santé et de la Recherche Médicale Paris France; Institut Curie Paris France; Mines ParisTech Fontainebleau Paris France; Paris Sciences et Lettres University Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Germany

Medical Faculty University of Cologne and University Hospital Cologne Cologne Germany

Molecular Oncology Laboratory Hospital Clinico San Carlos Instituto de Investigación Hospital Clínico San Carlos Centro de Investigación Biomédica en Red de Cáncer Martin Lagos Madrid Spain

North East Thames Regional Genetics Service Great Ormond Street Hospital for Children NHS Foundation Trust London United Kingdom

Oncogenetics Team The Institute of Cancer Research London United Kingdom

Service d'Oncogénétique Régional Poitou Charentes Centre Hospitalier Georges Renon Niort France

Unité d' Oncogénétique Centre Paul Strauss Strasbourg France

Université Claude Bernard Lyon 1 Villeurbanne France; Centre National de la Recherche Scientifique Unités Mixtes de Recherche Lyon France; Centre Léon Bérard Unité de Prévention et Epidémiologie Génétique Lyon France

West Midlands Regional Genetics Service Birmingham Women's and Children's NHS Foundation Trust Edgbaston Birmingham United Kingdom

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds United Kingdom

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