Next-generation sequencing reveals genetic heterogeneity and resistance mechanisms in patients withEGFR-mutated non-small cell lung cancer treated with afatinib

Abstract

BackgroundAfatinib, an irreversible ErbB family inhibitor, is widely used as first-line treatment in advanced lung adenocarcinoma patients harbouring mutant epidermal growth factor receptor (EGFR). With the advancements in next-generation sequencing (NGS), comprehensive research into the clinical impact of co-occurring genetic mutations and the molecular mechanisms of acquired resistance is required for afatinib users.MaterialsFrom January 2010 to December 2019, we enrolled patients with advanced lung adenocarcinoma withEGFRmutations using afatinib as first-line treatment, and we retrospectively collected pre- and post-afatinib treatment specimens from these patients for NGS testing.ResultsOf the 362 enrolled patients, 73 samples (68.9%) from 56 patients successfully returned complete NGS reports. In pre-afatinib treatment specimens, the most frequent co-occurring alterations wereTP53,MUC16,USH2A,SNYE1,RECQL4andFAT1; however, they were not related to progression-free survival. Small cell lung cancer transformation,EGFRp.T790M, amplification ofMET,ERBB2,KRAS,EGFR, cell cycle-regulated genes andMDM2, andPTENalterations were identified as acquired resistance mechanisms.EGFRp.T790M (p=0.0304) andAPCalterations (p=0.0311) in post-afatinib specimens were significantly associated with longer overall survival, whileMETamplification was significantly associated with poor overall survival (p=0.0324). The co-occurrence ofTP53alterations was significantly associated with shorter overall survival (p=0.0298).ConclusionsOur results show that the frequent co-occurring alterations in advancedEGFR-mutated lung adenocarcinoma did not influence the effectiveness of afatinib.EGFRp.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes.METamplification andTP53mutations were associated with poorer overall survival.