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Original Investigation
June 20, 2017

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

Author Affiliations
  • 1Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England
  • 2Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England
  • 3Centre for Epidemiology and Biostatistics, Melbourne School of Population Health, University of Melbourne, Melbourne, Australia
  • 4Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
  • 5Department of Medicine, St Vincent’s Hospital, University of Melbourne, Parkville, Australia
  • 6Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
  • 7Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 8Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 9Mathematics Institute, University of Warwick, Coventry, England
  • 10Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Australia
  • 11Inserm U900, Paris, France
  • 12Institut Curie, Paris, France
  • 13Mines ParisTech, Fontainebleau, France
  • 14PSL Research University, Paris, France
  • 15Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah
  • 16Department of Epidemiology, Columbia University, New York, New York
JAMA. 2017;317(23):2402-2416. doi:10.1001/jama.2017.7112
Key Points

Question  What are the breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers and are they related to family history of cancer and mutation position?

Findings  From a prospective cohort of 9856 mutation carriers, mainly ascertained through cancer genetic clinics, the cumulative breast cancer risk to age 80 years was 72% for BRCA1 and 69% for BRCA2 carriers. The cumulative ovarian cancer risk to age 80 years was 44% for BRCA1 and 17% for BRCA2 carriers. Cancer risks differed by cancer family history and mutation position.

Meaning  These findings provide cancer risk patterns based on BRCA status using prospective data. Family history and mutation position are important additional variables in risk assessment.


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.