The oncogenic role and clinical relevance ofBRCAmutations in NSCLC remain unclear. We aim to evaluate the characteristics and clinical outcomes of patients with NSCLC harboringBRCAmutations 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 somaticBRCAmutations (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.
BRCA突变在非小细胞肺癌（NSCLC）中的致癌作用及临床相关性尚不明确。本研究旨在评估哈达萨医疗中心（HMC）收治的携带BRCA突变的NSCLC患者的临床特征及治疗结局。我们回顾性分析了所有接受下一代测序（NGS）检测并发现携带致病性体细胞BRCA突变（p-BRCA）的晚期NSCLC患者，并将其与按年龄、分期、性别、吸烟史、PD-L1表达及驱动基因突变状态匹配的野生型BRCA（wt-BRCA）NSCLC患者进行临床结局比较。 2015年至2022年间，我们通过NGS检测评估了598例晚期NSCLC患者，其中26例（4.3%）携带p-BRCA突变。在这26例患者中，17例（65.4%）为胚系BRCA变异携带者，占HMC所有BRCA携带者的1%。患者诊断中位年龄为67岁（范围40-78岁），13例（50%）有吸烟史，9例（34.6%）合并其他驱动基因突变（EGFR、ALK、BRAF、MET或ERBB2）。 与wt-BRCA对照组相比，p-BRCA组患者接受一线铂类化疗的客观缓解率（72.2% vs 47.4%）和中位无进展生存期（16个月 vs 7个月；95% CI：5-22 vs 5-9）均显著更优，无进展生存期的风险比（HR）为0.41（95% CI：0.17-0.97）。p-BRCA组中有6例患者接受了后线聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）治疗，其中4例（66%）观察到持续缓解。 本队列研究表明，携带p-BRCA突变的NSCLC患者对PARPi具有高敏感性，并对铂类药物表现出持久治疗反应，提示BRCA突变在NSCLC中可能发挥一定的致癌作用。这些结果为开展PARPi治疗携带p-BRCA突变的NSCLC的前瞻性临床试验提供了依据。
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