The Impact of Mutations of BRCA1/2 Genes in Patients with Breast Cancer on Treatment Outcomes Following Radiation Therapy (RT)

Abstract

BRCA1/2 mutations in isolated cancer cells have been shown to enhance radiosensitivity, but it is not known if similar mutations in breast cancer (BC) patients yield improved responses to RT. We analyzed a large, national, previously unexamined dataset to determine if patients with BRCA1/2 mutations receiving RT achieve longer disease-free survival (DFS) and overall survival (OS) than patients with wild-type (WT) BRCA genes. The study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to select patients with Stage 0-III BC. Patients with known BRCA1/2 status were eligible if treated with RT≤ 1 year from diagnosis. Demographic data for patients with mutated and WT BRCA1/2 were compared using ANOVA and Chi-square tests. DFS was calculated from the start of RT until local/ distant recurrence or death and censored after the last clinic visit. Kaplan Meier estimates and multivariable Cox-proportional models (MVA) were used to compare DFS and OS for mutated and WT BRCA1/2 patients, for clinical stage, biomarkers (ER/PR/HER2), and surgery type (lumpectomy vs mastectomy). The study group of 1561 Stage 0-III BC patients included 1482 patients (95%) with WT BRCA and 79 patients (5%) with BRCA1/2 mutations (31 patients with a mutation of BRCA1, 46 patients with a mutation of BRCA2, and 2 patients with both mutations). Patients with BRCA1/2 mutations were younger (median: 51 vs 56, p = 0.004), diagnosed at higher clinical stage (Stage 0: 0% vs 0.2%, I: 31.6% vs 48.5%, II: 48.1% vs 34.0%, III: 20.3 vs 17.4%, p = 0.016), and more often grade 3 (60.8% vs 39.9%, p<0.001) than those with WT BRCA. Mastectomy was performed more often for patients with BRCA1/2 mutations (60.8% vs 31.5%, p<0.001). When BRCA1 and BRCA2 mutations were compared, BRCA1 patients were younger (median: 44 vs 52, p = 0.006), more often ER/PR negative (51.6% vs 13%, p<0.001), and had higher stage tumors (T1: 32.3% vs 47.8%; T2: 38.7% vs 28.3%, p = 0.032). On MVA, comparison of BRCA1/2 mutations vs WT BRCA identified no differences in DFS or OS. In spite of pre-clinical data demonstrating increased radiosensitivity for BRCA1/2-mutated BC cells lines, this large, previously unexamined dataset found BRCA1/2 mutations did not predict an improved OS or DFS for patients who received RT. When compared with WT BRCA patients, patients with BRCA1/2 mutations were found to have tumors of higher grade and clinical stage and to undergo more mastectomies. In a comparison with BRCA2-mutated patients, patients with mutations of BRCA1 were younger, more often ER/PR negative, and more likely to have high-stage tumors. The survival data and the advanced stage of BRCA1/2-mutated tumors suggest that the effect of BRCA1/2 mutations on radiosensitivity in vitro may be nullified by the aggressive behavior of BRCA1/2-mutated tumors in vivo.