BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

All Wales Medical Genetics Services University Hospital of Wales Cardiff United Kingdom

Center for Familial Breast and Ovarian Cancer Center for Integrated Oncology Medical Faculty University Hospital Cologne Cologne Germany

Center for Molecular Medicine Cologne University of Cologne Cologne Germany

Centre for Cancer Genetic Epidemiology Department of Oncology Strangeways Research Laboratory Worts Causeway University of Cambridge Cambridge United Kingdom

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

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

CLCC Antoine Lacassagne Département d'Hématologie Oncologie médicale Nice France

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

Département de biopathologie Oncogénétique clinique Centre François Baclesse Caen France

Département de Médecine Gustave Roussy Hôpital Universitaire Villejuif France

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Zluty kopec 7 Brno Czech Republic

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia Pennsylvania

Department of Clinical Genetics Maastricht University Medical Center Maastricht the Netherlands

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Genetics Royal Devon and Exeter Hospital Exeter United Kingdom

Department of Clinical Genetics VU University Medical Center Amsterdam the Netherlands

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

Department of Epidemiology Columbia University New York New York

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Genetics and Pathology Pomeranian Medical University Unii Lubelskiej 1 Szczecin Poland

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

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Medical Oncology Peter MacCallum Cancer Centre Melbourne Victoria Australia

Department of Medical Oncology Prince of Wales Hospital Randwick New South Wales Australia

Department of Medical Oncology St Vincent's Hospital Fitzroy Victoria Australia

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

Department of Medicine University of Utah Health Sciences Center Huntsman Cancer Institute Salt Lake City Utah

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

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

Department of Oncology Lund University Hospital Lund Sweden

Division of Cancer Epidemiology and Intelligence Cancer Council Victoria Melbourne Australia

Division of Cancer Medicine Peter MacCallum Cancer Centre Melbourne Victoria Australia

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

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

German Cancer Consortium Heidelberg Germany

Herbert Irving Comprehensive Cancer Center Columbia University Medical Center New York New York

Human Genetics Group Spanish National Cancer Centre Madrid Spain

Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City Utah

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin Poland

Inserm U830 Université Paris Descartes Paris France

INSERM U900 Paris France

Institut Curie Paris France

Institut Curie Service de Génétique Médicale Paris France

Institut Paoli Calmettes Département d'Anticipation et de Suivi des Cancers Oncogénétique Clinique and Aix Marseille Univ INSERM IRD SESSTIM Marseille France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Germany

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

Medical Genetics Unit St George's University of London London United Kingdom

Mines Paris Tech Fontainebleau France

Molecular Oncology Laboratory Hospital Clinico San Carlos IdISSC CIBERONC Madrid Spain

National Center for Tumor Diseases Partner Site Dresden Germany

Oxford Regional Genetics Service Churchill Hospital Oxford United Kingdom

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

PSL Research University Paris France

South East of Scotland Regional Genetics Service Western General Hospital Edinburgh United Kingdom

Stanford University School of Medicine Department of Medicine Division of Oncology and Stanford Cancer Institute Stanford University School of Medicine Stanford California

The Department of Oncology and Pathology Karolinska Institute Stockholm Sweden

The Sir Peter MacCallum Department of Oncology University of Melbourne Parkville Australia

Unité de prévention et Epidémiologie Génétique Centre Léon Bérard Lyon UMR CNRS 5558 Université de Lyon Lyon France

University of Cambridge Department of Medical Genetics NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Center Cambridge Biomedical Campus Cambridge United Kingdom

Wessex Clinical Genetics Service The Princess Anne Hospital Southampton United Kingdom

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