ATM Variants in Breast Cancer: Implications for Breast Radiotherapy Treatment Recommendations.

Abstract Purpose Advances in germline genetic testing have led to a surge in identification of ATM variant carriers among breast cancer patients, raising numerous questions regarding use of breast radiotherapy (RT) in this population. Methods A literature search utilizing PubMed identified articles assessing association(s) between germline ATM variant status and risk of toxicity following breast RT. An expert panel of breast radiation oncologists, genetic counselors and basic scientists convened to review the association between ATM variants and radiation-induced toxicity or secondary malignancy risk and determine any impact on breast RT recommendations. Results Carriers of pathogenic variants in ATM have a 2-4-fold increased risk for developing breast cancer. ATM variants do not consistently increase risk of toxicities following RT, except possibly among patients with the single nucleotide variant, c5557G>A (rs1801516) in whom a small increased risk for the development of both acute and late radiation effects has been identified. In most breast cancer patients with ATM variants, the excess 5-year absolute risk of developing a secondary contralateral breast cancer (CBC) following radiation is extremely low. The exception is in women younger than 45 years old with deleterious rare ATM missense variants, who may be at higher risk for developing a radiation-induced CBC over time. Conclusions Adjuvant radiation is safe for most breast cancer patients who harbor ATM variants. The possible exceptions are patients with the variant c5557G>A (rs1801516) and patients younger than 45 years old with certain rare deleterious ATM variants who may be at higher risk for developing CBC. These latter patients should be counseled regarding this potential risk, and every effort should be made to minimize contralateral breast dose. However, the inconsistency of published data limits precise recommendations, magnifying the need for further prospective study and the development of a centralized database cataloging RT outcomes and genetic status.