IMPORTANCE: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. OBJECTIVES: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. EXPOSURES: BRCA1/2 mutations, family cancer history, and mutation location. MAIN OUTCOMES AND MEASURES: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. RESULTS: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). CONCLUSIONS AND RELEVANCE: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

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

Centre de Lutte Contre le Cancer Georges François Leclerc Dijon France32Centre de Génétique Hôpital d'Enfants CHU Dijon Dijon France

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

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge England2Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton Cambridge England

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge England9Mathematics Institute University of Warwick Coventry England

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

Centre for Epidemiology and Biostatistics Melbourne School of Population Health University of Melbourne Melbourne Australia10Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population Health University of Melbourne Melbourne Australia4Division of Cancer Medicine Peter MacCallum Cancer Centre Melbourne Australia5Department of Medicine St Vincent's Hospital University of Melbourne Parkville Australia6Sir Peter MacCallum Department of Oncology University of Melbourne Parkville Australia

Centre François Baclesse Caen France

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

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

Department of Clinical Genetics Copenhagen University Hospital Rigshospital Copenhagen Denmark

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia Pennsylvania

Department of Clinical Genetics South Glasgow University Hospitals Glasgow Scotland

Department of Clinical Genetics St George's University of London London England

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 Cancer Prevention Institute of California Fremont

Department of Epidemiology Columbia University New York New York

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands8Department of Medical Informatics Academic Medical Center University of Amsterdam Amsterdam the Netherlands

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Gynaecology and Obstetrics University Hospital Carl Gustav Carus Dresden Germany50National Center for Tumor Diseases Partner Site Dresden Dresden Germany51German Cancer Consortium Dresden and German Cancer Research Center Heidelberg Germany

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge England

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

Department of Medicine 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 Canada41Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

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

Department of Obstetrics and Gynecology and Comprehensive Cancer Center Medical University of Vienna Vienna Austria61QIMR Berghofer Medical Research Institute Herston Australia

Department of Oncology and Pathology Karolinska Institute Stockholm Sweden

Department of Oncology Lund University Hospital Lund Sweden

Departments of Pedicatrics and Medicine Columbia University New York New York

Division of Cancer Medicine Peter MacCallum Cancer Centre Melbourne Australia58Department of Medical Oncology St Vincent's Hospital Fitzroy Australia

Family Cancer Clinic Netherlands Cancer Institute Amsterdam the Netherlands

Genetic Epidemiology Laboratory Department of Pathology University of Melbourne Parkville Australia

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

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

Human Genetics Group Spanish National Cancer Centre Madrid Spain46Biomedical Network on Rare Diseases Madrid Spain

Inserm U900 Paris France12Institut Curie Paris France13Mines ParisTech Fontainebleau France14PSL Research University Paris France

Institut Curie Department of Tumour Biology Paris France28Institut Curie INSERM U830 Paris France29Université Paris Descartes Sorbonne Paris Cité Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany48LIFE Leipzig Research Centre for Civilization Diseases University of Leipzig Leipzig Germany

Molecular Oncology Laboratory Hospital Clinico San Carlos Instituto de Investigación Sanitaria San Carlos Madrid Spain

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

Oncogénétique Clinique Hôpital René Huguenin Institut Curie Saint Cloud France

Prince of Wales Clinical School University of New South Wales Sydney Australia57Department of Medical Oncology Prince of Wales Hospital Randwick Australia

Unité d'Oncogénétique Centre Paul Strauss Strasbourg France

Unité de Prévention et d'Epidémiologie Génétique Centre Léon Bérard Lyon France

West Midlands Regional Genetics Service Birmingham Women's Hospital Healthcare NHS Trust Birmingham England

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds England

Citace poskytuje Crossref.org

Breast Cancer Occurrence After Risk-reducing Mastectomies in 274 Cases: A Single Center With More Than 42 Years of Experience

RAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer patient-derived xenograft models

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

Patient-reported outcomes in bilateral prophylactic mastectomy with breast reconstruction: A narrative review

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?

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

Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia

Uptake and Effectiveness of Risk-Reducing Surgeries in Unaffected Female BRCA1 and BRCA2 Carriers: A Single Institution Experience in the Czech Republic

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Cancer Spectrum, Family History of Cancer and Overall Survival in Men with Germline BRCA1 or BRCA2 Mutations

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

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

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Frequency of mutations in BRCA genes and other candidate genes in high-risk probands or probands with breast or ovarian cancer in the Czech Republic

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium