Practice Update | Onology

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Risks of breast, ovarian, and contralateral breast cancer for BRCA1- and BRCA2-

prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carri- ers. JAMA 2017 Jun 20;317(23)2402-2416, KB Kuchenbaecker, JL Hopper, DR Barnes, et al. 4) Mutation location matters – there are areas in the genes that are associated with rel- atively higher or lower risk of breast and ovarian cancer. All mutations are not equal. These results will aid the decision-mak- ing process for women identified as BRCA mutation carriers. Perhaps, most importantly, risk reduction bilateral salpingo-oophorec- tomy should be approached differently in BRCA1 vs 2 patients, while bilateral prophy- lactic mastectomy recommendations should probably be similar regardless of the gene involved. More accurate estimations of risk will reduce the uncertainty inherent in the shared decision-making process. Compre- hensive family history and careful analysis of the mutation location are important and are best accomplished by utilizing genetic counselors in the result delivery discussion when surveillance and treatment decisions are being made. COMMENT By Lee S. Schwartzberg MD, FACP W omen with hereditary BRCA1/2 mutations have an increased lifetime risk of developing breast cancer and ovarian cancer. With increased availability and affordabil- ity of testing, more women are being informed that they are mutation carriers. It is therefore critical to counsel them correctly as to their risk of developing these diseases and the timing of risk-re- ducing interventions such as surgery. For the first time, investigators have pub- lished in JAMA the results of a large prospective cohort study of BRCA1/2 muta- tion carriers, which clearly defines the risk of cancer with much less intrinsic bias and more precise estimates than previous retro- spective studies. Several findings stand out: 1) The cumulative lifetime risk of breast can- cer is high at about 70% to age 80 in both BRCA1 and -2 carriers, while the risk of ovarian cancer is far lower in BRCA2 than BRCA1 carriers. BRCA2 ovarian incidence does not begin until after age 50, while the risk starts at age 35 to 40 with BRCA1. For young carriers who wish to have chil- dren, this information is important. 2) Family history matters – there is approxi- mately a doubling of risk of breast cancer if at least one first-degree relative also has the disease. Similarly, family history of ovar- ian cancer increases the risk of that disease. 3) Contralateral breast cancer rates are high, up to 50% to 60% overall, but much lower for BRCA2 carriers if the first breast can- cer occurred after the age of 50 years.

mutation carriers JAMA: The Journal of the American Medical Association Take-home message

• This prospective study evaluated the impact of mutation type, location, and family history on the incidence and risk of breast, ovarian, and contralateral breast cancer. Analysis of 6030 BRCA1 female carriers revealed a rapid increase in the incidence of breast cancer until ages 30 to 40, which stabilized until age 80, resulting in a 72% cumulative risk of breast cancer in BRCA1 carriers. Analysis of 3820 BRCA2 carriers revealed an increasing incidence of breast cancer until age 40 to 50, which stabilizes through age 80, leading to a 69% cumulative risk of breast cancer in BRCA2 carriers. For BRCA1 and BRCA2 carriers up to 80 years of age, the cumulative risk of ovarian cancer was 44% and 17%, respectively, and the cumulative risk of contralateral breast cancer was 40% and 26%, respectively. There was a significant trend between the number of close relatives diagnosed with breast cancer and increased risk. • The study highlights the importance of mutation location and family history during risk assessment of breast cancer patients.

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 can- cer for mutation carriers and to evaluate risk modification by family cancer history and muta- tion 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 Can- cer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Famil- ial Breast Cancer, with ascertainment through family clinics (94%) and population-based stud- ies (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 fol- low-up was 5 years. EXPOSURES BRCA1/2 mutations, family cancer history, and mutation location. MAIN OUTCOMES AND MEASURES Annual inci- dences, standardized incidence ratios, and cumulative risks of breast, ovarian, and con- tralateral 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 analy- sis, 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 inci- dences 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 con- tralateral 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=0.001 for difference). Breast can- cer 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<0.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08–3.37; P=0.02 for trend). Breast can- cer risk was higher if mutations were located outside vs within the regions bounded by posi- tions c.2282–c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11–1.93; P=0.007) and c.2831–c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36–2.74; P<0.001). CONCLUSIONS AND RELEVANCE These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using

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