Risks of Breast, Ovarian, and Contralateral Breast Cancer for $\textit{BRCA1}$ and $\textit{BRCA2}$ Mutation Carriers

Abstract

$\textbf{Importance}$ The clinical management of $\textit{BRCA1}$ and $\textit{BRCA2}$ mutation carriers requires accurate, prospective cancer risk estimates.

$\textbf{Objectives}$ 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.

$\textbf{Design, Setting, and Participants}$ Prospective cohort study of 6036 $\textit{BRCA1}$ and 3820 $\textit{BRCA2}$ female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International $\textit{BRCA1/2}$ 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.

$\textbf{Exposures}$ $\textit{BRCA1/2}$ mutations, family cancer history, and mutation location.

$\textbf{Main Outcomes and Measures}$ Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer.

$\textbf{Results}$ 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 $\textit{BRCA1}$ and 69% (95% CI, 61%-77%) for $\textit{BRCA2}$ carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for $\textit{BRCA1}$ and until ages 40 to 50 years for $\textit{BRCA2}$ 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 $\textit{BRCA1}$ and 17% (95% CI, 11%-25%) for $\textit{BRCA2}$ carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for $\textit{BRCA1}$ and 26% (95% CI, 20%-33%) for $\textit{BRCA2}$ carriers (hazard ratio [HR] for comparing $\textit{BRCA2}$ vs $\textit{BRCA1}$, 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 $\textit{BRCA1}$ (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and $\textit{BRCA2}$ 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 $\textit{BRCA1}$ (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in $\textit{BRCA2}$ (HR, 1.93; 95% CI, 1.36-2.74; P<.001).

$\textbf{Conclusions and Relevance}$ These findings provide estimates of cancer risk based on $\textit{BRCA1}$ and $\textit{BRCA2}$ mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.