Background Heterozygous carriers with pathogenic germline variants in the ataxia-telangiectasia (ATM) gene are associated with increased cancer risk. While some reports suggest increased toxicity from radiation therapy (RT) among heterozygous ATM mutation carriers, the literature is conflicting. We performed a retrospective study of ATM mutation carriers with breast cancer to identify clinical factors that may impact risk of RT toxicity. Methods A retrospective chart review was conducted using the provincial British Columbia Hereditary Cancer Program electronic database to identify all breast cancer pts with heterozygous germline ATM mutations referred between January 1, 2000 to January 1, 2020. Germline genetic testing was expanded to routinely include ATM in 2019 for pts meeting testing criteria, and a subset of ATM-positive pts prior to 2019 were identified through updated testing. Pt data collected included age at diagnosis, pathologic features including grade, biomarker status, histologic subtype, stage, and treatment details. RT-related toxicity data were collected from the date of last RT treatment to date of last follow-up were classified retrospectively based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity was defined as acute if ≤6 months and chronic if >6 months after last RT treatment. Any toxicity grade ≥ 2 was considered clinically relevant. Results In total, 48 pts with pathogenic ATM germline mutations with a personal history of breast cancer were identified. Of these, 28 received RT to breast/chest wall and/or locoregional nodes between 1992-2020 and had evaluable records; 7 pts received RT of other anatomic sites, 13 pts did not receive any RT. Of the 28 ATM-positive pts who received locoregional RT, 19 (67.9%) had pathogenic and 9 (32.1%) had likely pathogenic ATM variants. The median time from last RT to last follow-up date was 91 months (range 4-257 months). The median time to first-reported acute and delayed toxicities grade ≥ 2 were 8 days and 18 months, respectively. Acute grade ≥ 2 toxicity was observed in 6/14 (43%) pts receiving conventional breast RT (≤2Gy/fraction) as compared to 5/14 (36%) pts who received hypofractionated breast RT (>2Gy/fraction). Four out of 28 pts (14%) who received locoregional breast RT developed recurrent disease (2 locoregional, 2 distant relapses). Among 20 ATM carriers who did not receive locoregional RT (n=7) or no RT (n=13), only 1 pt (5%) developed distant relapse. Of note, 5/13 (38%) pts who did not have adjuvant RT opted for completion mastectomies to avoid RT based on ATM status. Conclusions The overall frequency of RT grade ≥ 2 acute and/or chronic toxicity in ATM mutation carriers was 39% (11/28) and 18% (5/28), respectively. We did not identify a high frequency of severe (grade 3 or higher) acute or chronic RT toxicities among heterozygous carriers undergoing RT for breast cancer . The majority of acute and chronic toxicities were grade 2, and there were no reports of severe (grade 4 or 5) acute or chronic toxicities among pts receiving locoregional and/or non-locoregional RT. ATM-positive pts who received hypo-fractionated breast RT experienced fewer acute and chronic RT toxicities compared to those who received conventional breast RT, although the numbers were limited. In this retrospective study, there was no clear evidence of excessive severe toxicity among heterozygous ATM mutation carriers with breast cancer undergoing radiotherapy. Ongoing discussions are warranted between clinicians and ATM-positive pts to guide local treatment decision-making.

Citation Format: Brandon Lee, Elisa Chan, Phoebe T.M. Cheng, Scott Tyldesley, Kasmintan A. Schrader, Sophie Sun. Radiation toxicity in ATM mutation carriers with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-06.