Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial
Jordi Remon1, Benjamin Besse1,2, Alexandra Leary1,3
1Cancer Medicine Department, Gustave Roussy, Villejuif, France.
Introduction:
Molecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline BRCA1/2 mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of BRCA1/2 mutation in NSCLC remains poorly defined.
Methods:
From April 2014 to March 2017, 600 newly diagnosed, EGFR/ALK 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 BRCA1/2 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, BRCA1/2 variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic BRCA mutation. Two patients (0.5%) harbored a germline BRCA2 mutation, and for six others, a somatic BRCA mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. BRCA 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 BRCA mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months.
Conclusions:
Pathogenic BRCA1/2 mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of BRCA 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).
Insights
Pathogenic BRCA1/2 mutations are found in 2.1% of advanced NSCLC patients. However, BRCA mutations show limited predictive value for chemotherapy response in NSCLC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Molecular profiling is standard care for advanced non-small cell lung cancer (NSCLC).
- Next-generation sequencing can identify somatic or germline BRCA1/2 mutations as potential therapeutic targets.
- The clinical significance and therapeutic relevance of BRCA1/2 mutations in NSCLC are not well understood.
Purpose of the Study:
- To determine the prevalence of BRCA1/2 variants in advanced NSCLC patients.
- To assess the biological relevance and potential therapeutic implications of BRCA1/2 mutations in NSCLC.
Main Methods:
- Enrolled 600 EGFR/ALK-negative advanced NSCLC patients in the SAFIR02-Lung trial (April 2014-March 2017).
- Conducted molecular profiling using next-generation sequencing on tumor samples.
- Assessed BRCA1/2 variants, homologous recombinant deficiency (HRD) score, and germline status via blood analysis.
Main Results:
- BRCA1/2 variants were identified in 5.3% of profiled patients (379 total).
- Confirmed pathogenic BRCA mutations were found in 2.1% of patients (8/379), including 0.5% with germline BRCA2 mutations.
- Overall response rate to chemotherapy was 13% for patients with pathogenic BRCA mutations.
Conclusions:
- Pathogenic BRCA1/2 mutations occur in 2.1% of advanced NSCLC patients.
- The predictive role of BRCA mutations for NSCLC treatment decisions appears limited due to low platinum sensitivity and discrepancies in molecular features.
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