Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations

摘要

Background Identification of activated epidermal growth factor receptor ( EGFR ) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations. Methods We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM , ALK , KRAS , PIK3CA , PTEN , MET , IGF1R , and ROS1 , were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan–Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS. Results Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN ( P =?0.003 for PFS, and P =?0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations ( P ?0.001). A Cox proportional regression model determined that PTEN deletion (HR?=?4.29,95% CI?=?1.72–10.70) and low PTEN expression (HR?=?1.96, 95% CI?=?1.22–3.13), MET FISH?+?(HR?=?2.83,95% CI?=?1.37–5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor. Conclusions We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.