  Author information
1Centre 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.
2Centre for Epidemiology and Biostatistics, Melbourne School of Population Health, University of Melbourne, Melbourne, Australia.
3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
4Centre 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.
5Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
6Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands8Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
7Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England9Mathematics Institute, University of Warwick, Coventry, England.
8Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
9Centre for Epidemiology and Biostatistics, Melbourne School of Population Health, University of Melbourne, Melbourne, Australia10Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia.
10Inserm U900, Paris, France12Institut Curie, Paris, France13Mines ParisTech, Fontainebleau, France14PSL Research University, Paris, France.
11Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.
12Department of Epidemiology, Columbia University, New York, New York.
13Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
14Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
15Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
16Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
17Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, England.
18Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
19Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
20Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, England.
21West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, England.
22Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, England.
23Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, England.
24Oncogenetics Team, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, England.
25Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, Scotland.
26Department of Clinical Genetics, St George's, University of London, London, England.
27Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
28Oncogénétique Clinique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France.
29Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.
30Institut Curie, Department of Tumour Biology, Paris, France28Institut Curie, INSERM U830, Paris, France29Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
31Unité d'Oncogénétique, Centre Paul Strauss, Strasbourg, France.
32Centre de Lutte Contre le Cancer Georges François Leclerc, Dijon, France32Centre de Génétique, Hôpital d'Enfants, CHU Dijon, Dijon, France.
33Centre François Baclesse, Caen, France.
34Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
35Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands.
36Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
37Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
38Department of Epidemiology, Cancer Prevention Institute of California, Fremont.
39Departments of Pedicatrics and Medicine, Columbia University, New York, New York.
40Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada41Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
41Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia.
42Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
43Department of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah.
44Human Genetics Group, Spanish National Cancer Centre, Madrid, Spain46Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
45Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany48LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
46Department 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.
47Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany.
48Molecular Oncology Laboratory, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.
49Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
50Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec City, Québec, Canada.
51Prince of Wales Clinical School, University of New South Wales, Sydney, Australia57Department of Medical Oncology, Prince of Wales Hospital, Randwick, Australia.
52Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia58Department of Medical Oncology, St Vincent's Hospital, Fitzroy, Australia.
53Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
54Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
55Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria61QIMR Berghofer Medical Research Institute, Herston, Australia.
56Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
57Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
58Department of Clinical Genetics, Copenhagen University Hospital Rigshospital, Copenhagen, Denmark.
59Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
60Department of Oncology, Lund University Hospital, Lund, Sweden.
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Abstract
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.
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