BACKGROUND: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. METHODS: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. RESULTS: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). CONCLUSIONS: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

Cancer Epidemiology Centre Cancer Council Victoria Victoria Australia

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Strangeways Research Laboratory Worts Causeway Cambridge UK

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

Centre François Baclesse Caen France

CHU de Grenoble Hôpital Couple Enfant Département de Génétique Grenoble France

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

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic Center for Familial Breast and Ovarian Cancer Center for Integrated Oncology

Department of Clincial Genetics Rigshospitalet København Denmark

Department of Clinical Genetics Academic Medical Center Amsterdam the Netherlands

Department of Clinical Genetics and GROW School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht the Netherlands

Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands

Department of Clinical Genetics South Glasgow University Hospitals Glasgow UK

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

Department of Epidemiology

Department of Epidemiology Cancer Prevention Institute of California Fremont CA

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Gynaecologic Oncology University of Groningen University Medical Center 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 Prince of Wales Hospital Randwick Australia

Department of Medical Oncology St Vincent's Hospital Fitzroy Australia

Department of Medicine Huntsman Cancer Institute Salt Lake City UT

Department of Medicine St Vincent's Hospital University of Melbourne Parkville Victoria Australia

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of OB GYN and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Oncology Lund University Hospital

Department of Oncology Pathology Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

Department of Pathology and Molecular Medicine Juravinski Hospital and Cancer Centre McMaster University Hamilton Ontario Canada

Department of Pediatrics and Medicine Columbia University New York NY

Division of Cancer Medicine

Division of Population Science Fox Chase Cancer Center Philadelphia PA

Ecole des Mines de Paris ParisTech Fontainebleau France

Genetic Epidemiology Laboratory Department of Pathology

Genomic Medicine Manchester Academic Health Sciences Centre Institute of Human Development Manchester University Central Manchester University Hospitals NHS Foundation Trust Manchester UK

Genomics Center Centre Hospitalier Universitaire de Québec Research Center and Laval University Quebec City Quebec Canada

Hôpital Universitaire Dupuytren Service d'Oncologie Médicale Limoges France

Human Genetics Group Spanish National Cancer Centre Madrid Spain

INSERM U900 Paris France

Institut Curie Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Germany

Lund University Lund Sweden; Sir Peter MacCallum Department of Oncology

Medical Faculty University of Cologne and University Hospital Cologne Germany

Molecular Oncology Laboratory Hospital Clinico San Carlos IdISSC CIBERONC Martin Lagos s n Madrid Spain

North East Thames Regional Genetics Service Great Ormond Street Hospital for Children NHS Trust London UK

Oncogenetics Team The Institute of Cancer Research and Royal Marsden NHS Foundation Trust Sutton UK

Oncogénétique Clinique Institut Paoli Calmettes and Aix Marseille Univ INSERM IRD SESSTIM Marseille France

Oncology and Pathology Department of Clinical Sciences Lund

Oxford Regional Genetics Service Churchill Hospital Oxford UK

Precision Medicine School of Clinical Science at Monash Health Monash University Victoria Australia

Prince of Wales Clinical School University of New South Wales Sydney Australia

Service de Génétique Oncologique Hôpital René Huguenin Institut Curie Saint Cloud France

South East of Scotland Regional Genetics Service Western General Hospital Edinburgh UK

Stanford Cancer Institute Stanford University School of Medicine Stanford CA

Université Claude Bernard Lyon 1 Villeurbanne France

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds UK

Erratum In

JNCI Cancer Spectr. 2018 Aug 17;2(3):pky041. doi: 10.1093/jncics/pky041. PubMed

See more in PubMed

Kuchenbaecker KB, Hopper JL, Barnes DR et al. , . Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;31723:2402–2416. PubMed

Cibula D, Gompel A, Mueck AO et al. , . Hormonal contraception and risk of cancer. Hum Reprod Update. 2010;166:631–650. PubMed

Davidson BA, Moorman PG.. Risk-benefit assessment of the combined oral contraceptive pill in women with a family history of female cancer. Expert Opin Drug Saf. 2014;1310:1375–1382. PubMed

Gadducci A, Sergiampietri C, Tana R.. Alternatives to risk-reducing surgery for ovarian cancer. Ann Oncol. 2013;24(Suppl 8):viii47–viii53. PubMed

Lee E, Ma H, McKean-Cowdin R et al. , . Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: Results from a population-based study. Cancer Epidemiol Biomarkers Prev. 2008;1711:3170–3178. PubMed

Narod SA, Dube MP, Klijn J et al. , . Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2002;9423:1773–1779. PubMed

Walker JL, Powell CB, Chen LM et al. , . Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer. 2015;12113:2108–2120. PubMed

Goldgar D, Bonnardel C, Renard H et al. , . The International BRCA1/2 Carrier Cohort Study: Purpose, rationale, and study design. Breast Cancer Res. 2000;E10.

John EM, Hopper JL, Beck JC et al. , . The Breast Cancer Family Registry: An infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res. 2004;64:R375–R389. PubMed PMC

Phillips KA, Butow PN, Stewart AE et al. , . Predictors of participation in clinical and psychosocial follow-up of the kConFab breast cancer family cohort. Fam Cancer. 2005;42:105–113. PubMed

Thorne H, Mitchell G, Fox S et al. , . kConFab: A familial breast cancer consortium facilitating research and translational oncology. J Natl Cancer Inst Monogr. 2011;201143:79–81. PubMed

Antoniou AC, Goldgar DE, Andrieu N et al. , . A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol. 2005;291:1–11. PubMed

Bernholtz S, Laitman Y, Kaufman B et al. , . Cancer risk in Jewish BRCA1 and BRCA2 mutation carriers: Effects of oral contraceptive use and parental origin of mutation. Breast Cancer Res Treat. 2011;1292:557–563. PubMed

Brohet RM, Goldgar DE, Easton DF et al. , . Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: A report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol. 2007;2525:3831–3836. PubMed

Gronwald J, Byrski T, Huzarski T et al. , . Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat. 2006;952:105–109. PubMed

Haile RW, Thomas DC, McGuire V et al. , . BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev. 2006;1510:1863–1870. PubMed

Kotsopoulos J, Lubinski J, Moller P et al. , . Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers. Breast Cancer Res Treat. 2014;1433:579–586. PubMed

Ursin G, Henderson BE, Haile RW et al. , . Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res. 1997;5717:3678–3681. PubMed

Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1996;3479017:1713–1727. PubMed

Pike MC, Henderson BE, Casagrande JT et al. , . Oral contraceptive use and early abortion as risk factors for breast cancer in young women. Br J Cancer. 1981;431:72–76. PubMed PMC

Heemskerk-Gerritsen BA, Seynaeve C, van Asperen CJ et al. , . Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: Revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015;1075:djv033. PubMed

Kim J, Oktay K.. Baseline E(2) levels are higher in BRCA2 mutation carriers: A potential target for prevention? Cancer Causes Control. 2013;243:421–426. PubMed PMC

King MC, Wieand S, Hale K et al. , . Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;28618:2251–2256. PubMed

Mavaddat N, Barrowdale D, Andrulis IL et al. , . Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;211:134–147. PubMed PMC

Moorman PG, Havrilesky LJ, Gierisch JM et al. , . Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: A systematic review and meta-analysis. J Clin Oncol. 2013;3133:4188–4198. PubMed

Garcia C, Wendt J, Lyon L et al. , . Risk management options elected by women after testing positive for a BRCA mutation. Gynecol Oncol. 2014;1322:428–433. PubMed

Mannis GN, Fehniger JE, Creasman JS et al. , . Risk-reducing salpingo-oophorectomy and ovarian cancer screening in 1077 women after BRCA testing. JAMA Intern Med. 2013;1732:96–103. PubMed PMC

van Driel CM, Eltahir Y, de Vries J et al. , . Risk-reducing mastectomy in BRCA1/2 mutation carriers: Factors influencing uptake and timing. Maturitas. 2014;772:180–184. PubMed

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

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