Predictive and prognostic value of genetic aberrations of EGFR-TKI treatment: a real-world analysis of EGFR-mutant non-small cell lung cancer.

BACKGROUND

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for patients with EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). Although many patients benefit from targeted therapies, a significant proportion of patients experience suboptimal outcomes. The mechanisms underpinning this poor efficacy and the prognostic factors influencing outcomes remain insufficiently explored. This study aims to identify the genetic and clinical biomarkers that influence treatment efficacy in patients with advanced EGFRm NSCLC.

METHODS

Overall, 102 patients were enrolled. The clinical data of 77 patients with EGFRm NSCLC were retrospectively analyzed in a discovery cohort. Next-generation sequencing was performed using a lung cancer panel consisting of 139 genes. An external cohort of 690 patients with genetically profiled tissue samples from the cBioPortal database was used for external validation.

RESULTS

In the discovery cohort, the median progression-free survival (PFS) was 17.20 months and the median overall survival (OS) was 37.47 months. A history of smoking [hazard ratio (HR) 2.25, 95% confidence interval (CI): 0.99-5.12, P=0.046] and male sex (HR 2.18, 95% CI: 1.03-4.60, P=0.04) were significantly associated with poor outcomes. Treatment with third-generation EGFR-TKIs significantly prolonged PFS compared with first- and second-generation TKIs (HR 3.01, 95% CI: 1.17-7.73, P=0.02). EGFR copy number variations predicted shorter PFS across the different TKI generations. Patients with TP53 mutations exhibited poor OS (HR 8.74, 95% CI: 1.07-71.21, P=0.02), whereas those with CTNNB1 mutations exhibited good OS (HR 0.13, 95% CI: 0.02-1.02, P=0.02). In addition, higher maximum somatic allele fraction was correlated with a poor prognosis. The findings were validated in the external cohort.

CONCLUSIONS

This study identified key biomarkers associated with the efficacy of EGFR-TKIs and survival in patients with EGFRm NSCLC, thereby providing new insights for personalized therapeutic strategies based on genetic risk stratification.