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

Abstract

Afatinib, an irreversible ErbB Family inhibitor, is widely used as first-line treatment for advanced lung adenocarcinoma patients harboring with 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.From January 2010 to December 2019, we retrieved 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.Of 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,RECQL4, andFAT1; however, they were not related to progression-free survival. SCLC 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 (OS), whileMETamplification was significantly associated with poor OS (p=0.0324). The co-existence ofTP53alterations was significantly associated with a shorter OS (p=0.0298).Our results show that the frequent co-occurring alterations in advancedEGFR-mutant lung adenocarcinoma did not influence the effectiveness of afatinib.EGFRp.T790M is not only the major resistance mechanism to afatinib but also related to favorable survival outcomes.METamplification andTP53mutations were poor factors for OS.