Clinical Characteristics, Response to Platinum-Based Chemotherapy and Poly (Adenosine Phosphate-Ribose) Polymerase Inhibitors in Advanced Lung Cancer Patients Harboring BRCA Mutations

SIMPLE SUMMARY: Carriers of germline BRCA1/2 pathogenic variants are at increased risk of developing BRCA-associated malignancies (breast, ovarian, prostate and pancreatic cancer), which are responsive to treatment with poly (adenosine phosphate-ribose) polymerase inhibitors (PARPi) and platinum-based chemotherapy (PBC). However, the role of BRCA mutations in tumor development and in the prediction of response to treatment in nonsmall cell lung cancer (NSCLC) remains unclear. In this study, we retrospectively analyzed a cohort of 26 patients with NSCLC harboring BRCA mutations treated at our center, demonstrating unique clinical features, including many nonsmokers and BRCA mutations. Importantly, patients with NSCLC and BRCA mutations demonstrate increased sensitivity to PBC and PARPi in comparison to patients with NSCLC and wild-type BRCA. The results suggest that BRCA mutations play some oncogenic role in NSCLC and warrant further prospective trials of treatment of NSCLC harboring BRCA mutations with PARPi. ABSTRACT: The oncogenic role and clinical relevance of BRCA mutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboring BRCA mutations treated at Hadassah Medical Center (HMC). We retrospectively assessed all patients with advanced NSCLC who underwent next-generation sequencing (NGS) and were found to have pathogenic somatic BRCA mutations (p-BRCA). We compared clinical outcomes in NSCLC patients with wild-type BRCA (wt-BRCA) matched by age, stage, gender, smoking, PDL-1 and driver mutations. Between 2015 and 2022, we evaluated 598 patients with advanced NSCLC using NGS and found 26 patients with p-BRCA, of whom 17 (65.4%) were carriers of germline BRCA variants and represented 1% of all BRCA carriers HMC. The median age of diagnosis was 67 years old (40–78), 13 patients (50%) had a history of smoking and 9 patients (34.6%) had additional driver mutations (EGFR, ALK, BRAF, MET or ERBB2). Objective response rate and median progression-free survival (PFS) for first-line platinum-based chemotherapy in the p-BRCA group compared to wt-BRCA controls were 72.2% and 16 months (CI 95%, 5–22), compared to 47.4% and 7 months (CI 95%, 5–9), respectively, and HR for PFS was 0.41 (CI 95%, 0.17–0.97). Six patients in the p-BRCA group were treated with advanced-line poly (adenosine-phosphate-ribose) polymerase inhibitors (PARPi), with a durable response observed in four patients (66%). In this cohort, patients with NSCLC harboring p-BRCA exhibit high-sensitivity PARPi and a prolonged response to platinum, suggesting some oncogenic role for BRCA mutations in NSCLC. The results support further prospective trials of the treatment of NSCLC harboring p-BRCA with PARPi.