Clinical Toxicity in Hypofractionated and Conventionally Fractionated Radiation in Breast Cancer Patients with Germline ATM Mutations

Abstract

<h3>Purpose/Objective(s)</h3> The ataxia telangiectasia mutated (ATM) gene has significant roles in DNA double-strand break repair, and homozygous deficiency in ATM is known to cause significant sensitivity to ionizing radiation. Multigene panel testing has increasingly identified patients with ATM variants raising the question if those patients with heterozygous ATM variants are at increased risk of radiation toxicity. We hypothesize that there will be no significant difference in toxicity between hypofractionated (Hypo-RT) or conventionally fractionated (CRT) radiation treatments after breast conserving surgery (BCS) or mastectomy in patients with heterozygous germline ATM pathogenic variants or variants of uncertain significance (VUS). <h3>Materials/Methods</h3> Between 2004 and 2016, breast cancer patients treated with radiation were consented for peripheral blood sequencing (PBS). ATM variants detected by high-throughput PBS were designated benign, pathogenic, VUS, or with conflicting interpretations of pathogenicity using the ClinVar database. Variants designated benign or likely benign were excluded and those with conflicting interpretations of pathogenicity or variants of uncertain significance were classified as VUS. Toxicities were abstracted from medical records and were graded per Common Terminology Criteria for Adverse Events v5. Additional clinicopathologic information was abstracted from the medical records. Fisher's exact test was used to compare Grade 2 or 3 acute skin toxicity among patients with pathogenic variants or VUS treated with Hypo-RT versus CRT. <h3>Results</h3> A total of 400 patients were sequenced. After excluding benign ATM variants, 23 were included in this analysis, 2 (8%) were pathogenic and 21 (91%) were VUS. Median tumor size was 1.5cm and median age at diagnosis was 54 years (range: 33–74). Among these patients 91% had invasive disease, 72% were ER+, and 39% received chemotherapy; 86% elected for BCS with 78% undergoing sentinel lymph node dissection. All patients received photon based external beam radiation, 10 (43%) were treated with Hypo-RT, 12 (52%) with CRT, one (4%) with accelerated partial breast irradiation, and 4 (17%) with nodal irradiation. Median follow up was 5.04 years. Grade 2 acute radiation dermatitis (ARD) was noted in 8 patients (34%) and grade 3 in 2 patients (8%). There was no difference in Grade 2 or 3 ARD between patients receiving Hypo-RT or CRT (P= 0.4). Late grade 2 fibrosis was recorded in 1 patient (4%) and there were no events of any late grade 3 toxicity. Contralateral breast cancer occurred in 2 patients (8%) at 6 months and 9 years after the initial diagnosis. <h3>Conclusion</h3> Radiation treatment in patients with heterozygous ATM germline pathogenic or VUS appears well tolerated. In our study, there was no statistical difference in toxicity between Hypo-RT or CRT.