BRCA mutations detected by tumour next-generation sequencing in non-small cell lung cancer: impact on response to therapy and disease course

Abstract

Background Data regarding the prevalence and clinical relevance of BRCA mutations in non-small cell lung cancer (NSCLC) is limited. Our objective was to evaluate the impact of pathogenic BRCA variants detected by tumour next-generation sequencing (NGS) on disease course and response to therapy. Methods We performed a retrospective analysis of all consecutive NSCLC patients with available NGS reports in a single institution between 01/2015 and 08/2020. Pathogenicity of identified mutations was determined according to American College of Medical Genetics (ACMG) guidelines. Log rank and cox regression analyses were used to determine the association between BRCA mutation status, overall survival (OS) and progression-free survival (PFS) under various front-line treatment modalities for advanced disease. Results Out of 445 patients with NGS data (54% tissue, 46% liquid), 109 (24.5%) patients had a documented BRCA variant; 5.6% (25/445) had a pathogenic/likely pathogenic variant ( pBRCA ). Forty percent (10/25) of pBRCA patients had no co-occurring NSCLC driver mutations. Patients with pBRCA NSCLC had a less prominent smoking history [mean 42.6 (29.2) vs. 25.7 (24.0) pack years; P=0.024]. Median PFS with first-line chemo-immunotherapy was significantly prolonged for pBRCA patients (n=7) compared with wild-type BRCA ( wtBRCA ) patients (n=30) (HR =0.279; P=0.021, 95% CI: 0.094–0.825). Conclusions pBRCA -mutated NSCLC can represent a specific subtype of pulmonary carcinoma. Patients whose tumours harbor pBRCA mutations present with a less prominent smoking history and exhibit prolonged PFS with chemo-immunotherapy combinations compared with wtBRCA controls. In a subset of these patients, pBRCA is the sole identifiable putative driver mutation, hinting at a significant role for BRCA loss in oncogenesis.

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

“…The fact that, in our cohort, p-BRCA patients exhibited increased sensitivity to PBC and PARPi supports the assumption that, in at least some cases of NSCLC, mutations in BRCA play an oncogenic role and predict response to these treatments. These results also concur with the recent publication by Tschernichovsky et al, which showed prolonged PFS in first-line therapy for seven patients with NSCLC harboring BRCA mutations compared to an institutional cohort [23]. Two BRCA carriers in our cohort had additional somatic BRCA mutations; further HRD testing of tumor tissue samples, especially in cases in which sensitivity to PBC and PARPi was demonstrated, might shed light on the role of BRCA mutations in NSCLC.…”

“…This is likely due to the overrepresentation of the Ashkenazi-Jewish population at our center, where the estimated carrier frequency is 2.5% [22]. Indeed, 53.8% of patients in our study were carriers of classical Ashkenazi-Jewish PVs and the prevalence of p-BRCA in NSCLC patients in our study is similar to a recently published cohort of 445 patients with NSCLC treated in a different center in Israel [23]. The fact that only 1% of BRCA carriers at HMC developed NSCLC, together with the relatively older age of diagnosis (median 67 years old), corresponds with previous findings suggesting that BRCA carriers are not at increased risk for developing NSCLC [3,12,13].…”