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Background: Although breast cancer screening with mammography and magnetic resonance imaging (MRI) is recommended for breast cancer-susceptibility gene (BRCA) mutation carriers, there is no current consensus on the optimal screening regimen.Methods: The authors used a computer simulation model to compare 6 annual screening strategies (film mammography [FM], digital mammography [DM], FM and magnetic resonance imaging [MRI] or DM and MRI contemporaneously, and alternating FM/MRI or DM/MRI at 6-month intervals) beginning at ages 25 years, 30 years, 35 years, and 40 years, and 2 strategies of annual MRI with delayed alternating DM/FM versus clinical surveillance alone. Strategies were evaluated without and with mammography-induced breast cancer risk using 2 models of excess relative risk. Input parameters were obtained from the medical literature, publicly available databases, and calibration.Results: Without radiation risk effects, alternating DM/MRI starting at age 25 years provided the highest life expectancy (BRCA1, 72.52 years, BRCA2, 77.63 years). When radiation risk was included, a small proportion of diagnosed cancers was attributable to radiation exposure (BRCA1, <2%; BRCA2, <4%). With radiation risk, alternating DM/MRI at age 25 years or annual MRI at age 25 years/delayed alternating DM at age 30 years was the most effective, depending on the radiation risk model used. Alternating DM/MRI starting at age 25 years also produced the highest number of false-positive screens per woman (BRCA1, 4.5 BRCA2, 8.1).Conclusions: Annual MRI at age 25 years/delayed alternating DM at age 30 years is probably the most effective screening strategy in BRCA mutation carriers. Screening benefits, associated risks, and personal acceptance of false-positive results should be considered in choosing the optimal screening strategy for individual women. [ABSTRACT FROM AUTHOR]