Non- <i>BRCA</i> mutations in breast cancer: Shedding light on radiation outcomes.

e12582 Background: Multigene panel testing has advanced germline mutation detection in breast cancer, extending beyond BRCA 1/2. However, the impact of radiotherapy (RT) on patients with non- BRCA pathogenic variants remains unclear. Most studies focus on BRCA 1/2, leaving other mutations understudied. This study evaluates treatment-related toxicity following adjuvant RT in genetically tested patients. Methods: This is a retrospective study of 67 patients with non-metastatic breast cancer diagnosed between 2015-2024 who underwent surgery, radiotherapy (breast/chest wall ± nodal irradiation), and multigene panel testing. Chi-square tests compared gene groups, and Firth logistic regression analyzed associations between mutations, radiation parameters (dose, boost, technique), and the incidence of acute/chronic toxicity and secondary malignancies. Statistical significance was set at P &lt; 0.05. Results: The cohort included patients with non-BRCA mutations: ATM (n=20), CHEK2 (n=20), PALB2 (n=13), TP53 (n=11) and PTEN (n=3). The median follow-up was 34 months, with a median age of 44 years and 5% presenting with synchronous breast cancer at diagnosis. Hormone receptor positivity was high (ER 95.5%, PR 83.6%), and 31.3% were HER2-positive. Disease stages included DCIS (11.9%), Stage I (31.3%), Stage II (31.3%), and Stage III (25.4%). Mastectomy was performed in 64.2%, while 35.8% underwent breast-conserving surgery. Regarding radiation techniques, forward planning was used in 58 patients (86.6%), and VMAT in 9 (13.4%). Skin toxicity was the most common adverse effect, with acute toxicity observed in 91.0%, predominantly Grade I (77.6%) and Grade II (11%), while one TP53 patient experienced Grade III toxicity and no grade IV acute toxicity. Acute toxicity rates were 46.3% with conventional fractionation, 44.8% with hypofractionation, and none with ultra-hypofractionation. Chronic toxicity was primarily skin-related (6%, Grades I-III), with one TP53 patient developing Grade IV skin toxicity. Second malignancies occurred in 9% of cases, with contralateral breast cancer being the most frequent (3%). Importantly, none of these malignancies were radiation-induced. Conclusions: These findings are consistent with the outcomes reported in patients with non-germline mutations described in the literature. Reinforcing the safety of radiotherapy in patients with non- BRCA pathologic variants, regardless of dose, fractionation, and technique. Counseling patients on the risk of second malignancies, especially contralateral breast cancer, is essential for informed decision-making.