Abstract PS1-07-21: Germline Genetic Variants and Risk of Acute Radiation Dermatitis in Patients Receiving Curative-Intent Radiation Therapy for Breast Cancer

Abstract Background: Multigene panel testing has increased the detection of pathogenic germline variants (PV) in patients with breast cancer. The impact of PVs and variants of unknown significance (VUS) on toxicity and clinical outcomes has largely been studied in patients with BRCA1 or BRCA2 mutations, with few data on patients with other genetic alterations. In addition, few studies have characterized the impact of VUS on toxicity and/or outcomes. At our institution, a prospective Precision Medicine study was started to characterize germline and somatic mutations in breast cancer patients. Here, we present a preliminary analysis of acute toxicity rates in breast cancer patients treated with curative intent radiation therapy based on germline mutation status. Materials/Methods: This retrospective, single-institution study utilized the Precision Medicine database at our institution to identify breast cancer patients with available genetic data. Among 4400 patients with stage I-IV breast cancer, 900 received curative-intent breast radiotherapy (RT). Clinicodemographic information, RT parameters, and germline mutation status - characterized as PV, VUS, or benign - were extracted from the database. RT toxicity was prospectively documented in the electronic medical record (EMR) during the study period. The primary endpoint was the incidence of acute grade 2 or higher radiation dermatitis (G2RD). Associations between germline mutational status and toxicity rates were evaluated using the chi-square test, with significance defined as p<0.05. Results: Of the 900 patients in the Precision Medicine database who received breast RT, 396 had complete clinical, RT, and genomic data available. The median age is 57 years (IQR 47-65), with 37% Hispanic, 40% non-Hispanic White, and 15% non-Hispanic Asian. Disease stage was 29% stage I, 50 % stage II, and 17% stage III. Breast cancer subtypes were 68% HR+/HER2-, 17% HER2+, and 15% triple negative. Breast-conserving therapy was performed in 65% of cases. Radiation was delivered to the whole breast in 46% (N=182), breast/chest wall plus regional nodes (PMRT/RNI) in 45% (N=177), accelerated partial breast irradiation (APBI) in 4%, and intraoperative radiation therapy (IORT) in 5% of patients. Hypofractionated RT (≥2.66 Gy/fraction) was delivered to 45% of patients. Germline testing identified 10% PV (N=39), 57% with VUS in at least one gene (N=224), and 33% Benign (N=133). The overall incidence of G2RD was 24% (N=95) and did not differ based on germline mutation status: 28.2% for PV, 22% for VUS, and 26% for benign status (p=0.64). Among patients with PV, BRCA1/2 mutations were the most common (N=11), with a G2RD rate of 18%, similar to the entire population. MUTHY mutations were the next most common (N=9), with 0% G2RD. The one patient with PALB2 mutation did not have G2RD and no CHK2 or ATM mutations were present in the analyzed cohort. Factors significantly associated with increased G2RD were the type of RT delivered (31% in the PMRT/RNI group, 21% for whole breast only, and 3% for APBI/IORT; p=0.0006) and fractionation schedule (31.9% for conventionally fractionated RT vs 14.5% in hypofractionated RT; p<0.0001). Conclusion: In this preliminary analysis, germline pathogenic mutations or variants of unknown significance were not associated with an increased risk of acute radiation dermatitis compared to those with benign mutation status. As expected, only factors related to RT delivery were associated with the development of grade 2 dermatitis. Ongoing analysis will assess these findings in the complete dataset and evaluate local-regional recurrence by germline and somatic mutation status. Citation Format: N. Eustace, K. Ghaffarian, T. Watkins, K. Vo, L. Reynaga, J. Bonner, S. Gruber, T. Williams, J. Bazan. Germline Genetic Variants and Risk of Acute Radiation Dermatitis in Patients Receiving Curative-Intent Radiation Therapy for Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-07-21.