PT  - JOURNAL ARTICLE
AU  - Liang, Sheng-Kai
AU  - Wei, Pin-Fei
AU  - Hsieh, Min-Shu
AU  - Wu, Chia-Ling
AU  - Shih, Jin-Yuan
TI  - Next-generation sequencing reveals genetic heterogeneity and resistance mechanisms in patients with <em>EGFR</em>-mutated non-small cell lung cancer treated with afatinib
AID  - 10.1183/23120541.00676-2023
DP  - 2024 Mar 01
TA  - ERJ Open Research
PG  - 00676-2023
VI  - 10
IP  - 2
4099  - http://openres.ersjournals.com/content/10/2/00676-2023.short
4100  - http://openres.ersjournals.com/content/10/2/00676-2023.full
SO  - erjor2024 Mar 01; 10
AB  - Background Afatinib, 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.Materials From January 2010 to December 2019, we enrolled patients with advanced lung adenocarcinoma with EGFR mutations using afatinib as first-line treatment, and we retrospectively collected pre- and post-afatinib treatment specimens from these patients for NGS testing.Results 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 were TP53, MUC16, USH2A, SNYE1, RECQL4 and FAT1; however, they were not related to progression-free survival. Small cell lung cancer transformation, EGFR p.T790M, amplification of MET, ERBB2, KRAS, EGFR, cell cycle-regulated genes and MDM2, and PTEN alterations were identified as acquired resistance mechanisms. EGFR p.T790M (p=0.0304) and APC alterations (p=0.0311) in post-afatinib specimens were significantly associated with longer overall survival, while MET amplification was significantly associated with poor overall survival (p=0.0324). The co-occurrence of TP53 alterations was significantly associated with shorter overall survival (p=0.0298).Conclusions Our results show that the frequent co-occurring alterations in advanced EGFR-mutated lung adenocarcinoma did not influence the effectiveness of afatinib. EGFR p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. MET amplification and TP53 mutations were associated with poorer overall survival.Co-occurring mutations do not hinder afatinib's effectiveness in EGFR-mutated NSCLC. EGFR p.T790M predicts better outcomes, while MET amplification and TP53 mutations indicate poorer OS. https://bit.ly/3vydDiy