Three New Disease-progression Modes In NSCLC Patients After EGFR-TKIs Treatment By Next-Generation Sequencing Analysis

Objective:For advanced non-small cell lung cancer(NSCLC)patients who have mutations in the epidermal growth factor receptor(EGFR)gene,several studies have demonstrated that the efficacy of EGFR tyrosine kinase inhibitors(EGFR-TKIs)is significantly superior to traditional platinum-based dual drugs chemotherapy.However,most patients will inevitably develop disease progression after 9-13 months of treatment with EGFR-TKIs.With the in-depth study of molecular characteristics of lung cancer and the rapid development of genetic testing technology,it enables people to have a clearer understanding of the molecular mechanisms of lung cancer development at the genetic level.Herein,based on next-generation sequencing(NGS),our study aimed to investigate the clinical characteristics,genetic variation,prognosis and follow-up treatment of three new disease-progression modes after taking EGFR-TKIs.Methods:Patients with sensitive EGFR-mutations who treated with EGFR-TKIs at Jinling Hospital from July 2015 to October 2017 were retrospectively analyzed.Patients meeting the following criteria were included:(1)histology or cytology confirmed as advanced NSCLC;(2)developed radiographic progression after taking first-,second-or third-generation EGFR-TKIs;and(3)patients whose tissues were used for post-progression NGS.Finally,41 patients were eligible for inclusion in our study.According to the characteristics of radiographic progression of these 41 patients,they were divided into three groups:progression of primary foci,progression of metastatic foci,progression of dual primary and metastatic foci.The NGS testing results of three groups were obtained to analyze the gene expression heterogeneity and the primary endpoint of this study was progression-free survival.We used SPSS 22.0 statistical software for data analysis,not only studied the clinical characteristics of three different disease progression modes and the efficacy of EGFR-TKIs treatment,but also deeply analyzed the heterogeneity of gene expression in three modes and provided clinical strategies for follow-up treatment.Results:After reading the imaging data,41 patients were divided into three groups,including 8 cases(19.5%)in the primary foci progression mode(Mode 1),13 cases(31.7%)in the metastatic foci progression mode(Mode 2),and 20 cases(48.8%)in the dual primary and metastatic foci progression mode(Mode 3).The median PFS was 6 months in Mode 1,significantly lower than the 11 months in Mode 2 and 10 months in Mode 3(P=0.0084).In addition,we analyzed the expression of EGFR 19Del,EGFR L858R,EGRF T790M and TP53 in three modes and found that there was a significant difference in the expression of EGFR 19Del mutation in three groups(P=0.02).The numbers and types of gene mutation in Mode 3 were significantly higher than those in Mode 1 and 2,and we did not observe gene amplifications in Mode 2.TP53 mutation was the gene with the highest mutation frequency found in this study,accounting for 48.8%(20/41)of all mutations.The mutation sites of TP53 in Mode 1 were mainly in exons 6 and 8,while in Mode 2 and 3 were located on exons 4/5/6/7/8.Finally,Cox multivariate and univariate regression analysis suggested that age,gender,smoking status,stage,platelet count,baseline EGFR mutation,and treatment options were not independent factors of PFS.Conclusion:Our study explored three new disease-progression modes after EGFR-TKIs treatment in NSCLC patients by next-generation sequencing analysis.Compared with the primary foci progression mode,a significant benefit of PFS can be observed in the metastatic foci progression mode and the dual primary and metastatic foci progression mode,which has important reference value for the future clinical therapeutic strategies.