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Purpose: Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM.Methods and Materials: Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with ≥5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined.Results: Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma.Conclusions: In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers. [ABSTRACT FROM AUTHOR]