Susan G R McDuff1, Jennifer R Bellon2, Kristen M Shannon3, Michele A Gadd4, Samantha Dunn5, Barry S Rosenstein6, Alice Y Ho7. 1. Duke Cancer Center, Department of Radiation Oncology, Duke Cancer Center, Durham, North Carolina. 2. Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. 3. Cancer Center Genetics Program, Massachusetts General Hospital, Boston, Massachusetts. 4. Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. 5. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. 6. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: alice.ho@mgh.harvard.edu.
Abstract
PURPOSE: Advances in germline genetic testing have led to a surge in identification of ataxia-telangiectasia mutated (ATM) variant carriers among breast cancer patients, raising numerous questions regarding use of breast radiation therapy (RT) in this population. METHODS: A literature search using PubMed identified articles assessing association(s) between the germline ATM variant status and the risk of toxicity after 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 to determine any impact on breast RT recommendations. RESULTS: Carriers of pathogenic variants in ATM have a 2- to 4-fold increased risk for developing breast cancer. ATM variants do not consistently increase risks of toxicities after 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) after 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 the contralateral breast dose. However, the inconsistency of published data limits precise recommendations, magnifying the need for further prospective studies and the development of a centralized database cataloging RT outcomes and genetic status.
PURPOSE: Advances in germline genetic testing have led to a surge in identification of ataxia-telangiectasia mutated (ATM) variant carriers among breast cancerpatients, raising numerous questions regarding use of breast radiation therapy (RT) in this population. METHODS: A literature search using PubMed identified articles assessing association(s) between the germline ATM variant status and the risk of toxicity after 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 to determine any impact on breast RT recommendations. RESULTS: Carriers of pathogenic variants in ATM have a 2- to 4-fold increased risk for developing breast cancer. ATM variants do not consistently increase risks of toxicities after 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 cancerpatients with ATM variants, the excess 5-year absolute risk of developing a secondary contralateral breast cancer (CBC) after 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 cancerpatients 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 the contralateral breast dose. However, the inconsistency of published data limits precise recommendations, magnifying the need for further prospective studies and the development of a centralized database cataloging RT outcomes and genetic status.