Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial.

INTRODUCTION

Molecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of mutation in NSCLC remains poorly defined.

METHODS

From April 2014 to March 2017, 600 newly diagnosed, negative patients with advanced NSCLC were enrolled in the SAFIR02-Lung trial. Molecular profiling was done at study entry on archival tissue or frozen tissue collected from a new biopsy specimen before the third cycle of platinum-based chemotherapy. The prevalence of variants and its biological relevance were assessed. A homologous recombinant deficiency (HRD) score was based on the copy number variation data, and the germline status was determined by blood analysis. The BRCA Share database and the French CGG consortium were the references for the variant classification.

RESULTS

Of 379 patients with a molecular profile discussed in a tumor molecular board, variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic mutation. Two patients (0.5%) harbored a germline mutation, and for six others, a somatic mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. variants of unknown significance were detected in 12 patients (3.2%), achieving an 8.3% overall response rate with chemotherapy. One-third of tumors carrying pathogenic mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months.

CONCLUSIONS

Pathogenic mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of mutation for making treatment decisions in NSCLC seems limited based on clinical response (low platinum sensitivity) and molecular features (discrepancy between biallelic inactivation and high HRD score).