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

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%confi-dence 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.