Abstract A59: Impact of NGS four-gene panel in screening genes with potential therapies in NSCLC
Authors: Carolina Bustamante, Maíra Cristina Menezes Freire, Natália Penido Lopes, Mariano Zalis
Journal: Clinical Cancer Research (2018)

Abstract Targetable genomic mutation detection has innovated personalized medicine in non-small cell lung cancer (NSCLC) mainly through detection of EGFR activation mutations, which predicts susceptibility to tyrosine kinase inhibitors (TKIs). Although patients render positive response to TKIs initially, resistance could eventually arise, due to the secondary mutation T790M, therefore decreasing patients' survival and limiting treatment options. NSCLC patients harbors a variety of other mutated genes, despite EGFR that could potentially be treated with drugs already approved, or in ongoing clinical trials for other types of tumor. KRAS is one of the most frequently mutated genes in NSCLC and could act as a new target for lung cancer treatment. Although no targeted therapy has yet been approved for mutated-KRAS, there are multiple potential treatment strategies under investigation. BRAF is another gene described in NSCLC that offers a rational therapeutic strategy, since its pathway plays a role in the carcinogenesis of NSCLC. In the present study the prevalence of KRAS, BRAF, and EGFR was determined among patients with next-generation sequence technology. We used a custom multigene panel for Ion Platform to investigate EGFR, KRAS, and BRAF mutations in 491 NSCLC Brazilian patients. Genomic DNA libraries were prepared from FFPE-derived DNA and sequenced in the Ion PGM platform. KRAS was the most frequently mutated gene, found in 27.6% of all samples, and thus could be an appealing target for new therapy strategies as described in other studies. 111 (82.2%) samples harbored mutation in codon 12, with G12C mutation the most common one, present in 37.8%. The second most prevalent mutated gene was EGFR with 119 (24.3%) mutated samples. The most common mutations were exon 19 deletions (most frequently E746-A750), found in 42% of the samples, and L858R, found in 32% of the samples. BRAF displayed prevalence rates of 3.7%. V600E mutation was present in 55.5% of the BRAF mutated samples, followed by mutations in codon G469 (22%). We identified 17 double and coexisting mutations. EGFR T790M was the most common secondary mutation, found in six (12%) samples concomitantly with p.E746_A750del, indicating that these patients might have a reduced response to TKIs therapy. Interesting is the fact that three of these double mutant samples had prior cobas® EGFR Test results from 2-3 previous years with absence of T790M mutation, indicating that resistance may have arrived in a 2- to 3-year life span. Although EGFR gene mutations are reported as mutually exclusive with KRAS or BRAF mutations in lung cancer, we found three samples harboring concomitant EGFR and KRAS mutations. Previous studies also reported that mutations in KRAS and BRAF are mutually exclusive, but we found one sample harboring mutations in both genes, indicating that this is a rare event. In conclusion, this study shows that in development of future therapies, targeting KRAS should be prioritized. Although BRAF-mutated samples displayed short prevalence, it could be a potential target among wild-type EGFR and KRAS cancer patients. This study shows the importance of multi-gene panel screening to reduce overall turnaround time generating results in a single test. Citation Format: Carolina Bustamante, Maíra Cristina Menezes Freire, Natália Penido Lopes, Mariano Zalis. Impact of NGS four-gene panel in screening genes with potential therapies in NSCLC [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A59.