Structural classification of EGFR mutations and its association with TKI efficacy against compound and co-mutations in a Chinese NSCLC cohort: a single-center retrospective analysis

Epidermal growth factor receptor( EGFR )mutations have been classified into four distinct subgroups based on the characteristics of the kinase domain and their sensitivity to tyrosine kinase inhibitors (TKIs).However, literature regarding the distribution and biological features of these structural subtypes among Chinese patients with non-small cell lung cancer (NSCLC) remains limited.This retrospective study aims to further investigate the distribution characteristics of EGFR mutations and the sensitivity of complex EGFR mutations to TKIs in Chinese patients. A total of 452 patients diagnosed with NSCLC were enrolled in this study. All samples were screened for EGFR , KRAS , ALK , ROS1 , MET , ERBB2 , RET , BRAF , and NTRK1/2/3 mutations using next-generation sequencing (NGS). EGFR mutations were systematically categorized into four subgroups based on the structural classification method. Drug sensitivities to various EGFR- TKIs were analyzed separately in 28 patients with compound EGFR mutations and 39 patients with EGFR co-mutations. Additionally, the correlation between driver gene mutations and clinicopathological characteristics was also evaluated. Approximately 81.64% of patients with NSCLC harbored at least one gene alteration, the three most frequent genomic alterations were EGFR (53%), KRAS (13%), and ALK (11%). Among EGFR -mutant patients, 80.33% were classical-like, 6.69% were T790M-like, 3.35% were Ex20ins-L, and 4.60% were PACC. Predominantly, L858R and exon 19 deletions(19del)accounted for 50% and 46.88% of classical-like mutations, respectively. Compared with patients harboring a single classical EGFR mutation, those with compound EGFR mutations had worse clinical response to first-line TKIs ( P = 0.022), and patients with co-occurring EGFR mutations also exhibited poorer sensitivity to TKIs ( P = 0.045). Statistical analysis indicated that the EGFR mutation rate was significantly higher in females and in patients with adenocarcinoma. ALK mutations were significantly positively correlated with tumor site and lymph node metastasis, and male patients were more likely to harbor RET mutations. EGFR mutations were predominantly of the classical-like type in Chinese patients with NSCLC. Our results also confirm that EGFR compound mutations and co-mutations reduce the efficacy of various TKIs. These findings will facilitate drug development and personalized targeted therapy.