Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

Abstract Background: Lung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cancer characterized by driver mutations detected in a substantial proportion of the cases. Tyrosine kinase inhibitors (TKIs) are standard care for the patients with these mutations. In this study, we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive Chinese LUAD patients who are treatment-naïve. Material and methods: Targeted sequencing covering the hotspot regions of eight LUAD driver genes was performed across 853 treatment-naïve LUAD patients. Logistic regression analysis was used to determine the factors associated with presence of these mutations. Genetically modified LUAD PC9 cells were established to evaluated the sensitivity of selected EGFRcompound mutations to different EGFR-TKIs in-vivo. Results: A total of 574 single nucleotide variants, 270 InDels, 88 amplifications, and 87 rearrangements were identified in this study, with EGFR and KRAS being the most frequently mutated genes. Females, mostly life-long non-smokers, had significantly higher EGFRmutation rates than males and had a T>A conversion signature, for which the etiological factor is still unknown. Males, primarily smokers, more frequently had KRAS mutations and a smoking-associated signature of C>A conversions. Rare EGFR compound mutations identified in this study (Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873) conferred genetically modified PC9 cells, constantly and consistently, more sensitive to second-generation EGFR-TKI afatinib in-vivo. Conclusion: Over 70% of Chinese treatment-naïve LUAD patients are TKIs-targetable. Patients with rare EGFR compound mutations might conside second-generation EGFR-TKIs for treatment.