Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.
Level 3 - non-randomized controlled study
Prospective cohort study evaluating cancer incidence in mutation carriers
PubMed 28632866 · doi:10.1001/jama.2017.7112
What was done
Prospective cohort study of 6,036 BRCA1 and 3,820 BRCA2 female carriers (5,046 unaffected and 4,810 with breast or ovarian cancer at baseline) recruited between 1997 and 2011 from international consortia, primarily through family clinics (94%) and population-based studies (6%), with median follow-up of 5 years. Age-specific incidences and cumulative risks to age 80 were evaluated for breast cancer (3,886 eligible), ovarian cancer (5,066 eligible), and contralateral breast cancer (2,213 eligible), assessing risk modification by family history and mutation location.
What was found
During follow-up, 426 incident breast, 109 ovarian, and 245 contralateral breast cancers occurred. Cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2. Annual breast cancer incidence plateaued at 20-30 per 1,000 person-years between ages 30-40 for BRCA1 and 40-50 for BRCA2. Cumulative ovarian cancer risk to age 80 was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2. Contralateral breast cancer 20-year cumulative risk was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 (HR comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82). Breast cancer risk was significantly higher with 2 or more versus 0 affected relatives for BRCA1 (HR 1.99; 95% CI, 1.41-2.82) and BRCA2 (HR 1.91; 95% CI, 1.08-3.37). Risk was also higher if mutations were located outside versus within specific central regions: c.2282-c.4071 for BRCA1 (HR 1.46; 95% CI, 1.11-1.93) and c.2831-c.6401 for BRCA2 (HR 1.93; 95% CI, 1.36-2.74).
Why it matters
This study provides reliable prospective estimates of breast, ovarian, and contralateral breast cancer risks in BRCA1/2 carriers, establishing that mutation position and family history provide meaningful risk stratification for clinical counseling.
Limits
The cohort was largely ascertained through clinical genetics services (94%), which may lead to higher risk estimates than in unselected population carriers. Median follow-up was modest at 5 years, and participants were predominantly from Western European cohorts (UK, Netherlands, France).
Cited by
- supports BRCA mutations predispose individuals to breast cancer and other forms of cancer.
- supports BRCA mutations account for only a small minority of overall cancers, but confer a very high individual lifetime cancer risk to carriers.