Impact of co-occurring genomic alterations on overall survival of BRAF V600E and non-V600E mutated NSCLC patients: Results of the Network Genomic Medicine

Abstract

Background: Activating BRAF mutations are found in 1-3% of lung adenocarcinomas. Treatment with a combination of a BRAF- and a MEK-inhibitor is now the approved standard therapy for V600E mutated patients. The molecular co-alterations that drive the heterogeneity of BRAF mutated lung cancer patients (pts) are poorly characterized by the lack of multiplex diagnostics results. Frequently used single gene tests are unable to detect co-occurring mutations and their mutual impact on overall survival. The Network Genomic Medicine (NGM) performs high sensitive next generation sequencing (NGS) based diagnostics on a central platform in Cologne for inoperable lung cancer pts in Germany. Methods: The NGS panel used inNGM consists of 17 genes to cover potentially targetable aberrations and is run on Illumina (MySeq) platform. In 2016, we have started the retrospective evaluation of BRAF mutated pts with available clinical data and given consent who had received NGS-based molecular diagnostics. In particular, we have focused on BRAF V600E and non-V600E mutated lung cancer pts with and without cooccurring mutations: their frequency, significance and impact on overall survival. Results: Wehave analyzed 174 pts (V600E=55 pts, non-V600E=119 pts)with eligible clinical data. Co-occurringmutations were detected in 121 BRAFmutated pts (70%). Themost frequent co-alteration was found in TP53 for 89 pts (74%). Regardless of treatment regime, BRAF mutated lung cancer pts without co-alterations seem to have a better overall survival (OS) with 15 versus 13 month (p=0.463), same data for the TP53 co-mutated pts (p=0.449). Likewise, non-targeted treatment ofV600Emutation seems to be a negative prognostic factor with OS=15month versus 22month in non-V600Emutated pts (p=0.957). Conclusions: We report for the first time to our knowledge the heterogeneity of BRAF mutated lung cancer pts in the largest cohort. This work provides evidence that cooccurring genomic alterations influence the overall survival of these pts and stresses the relevance of the multiplex genotyping. Further data including therapies, co-alterations in V600E and other clinicopathologic parameters will be provided.