Clinical Characteristics Of EGFR Single Gene Mutation And Multi-gene Coexisting Mutation In Advanced Non-small Cell Lung Cancer And The Efficacy Of EGFR-TKIs

Background and purpose:The incidence and mortality of non-small-cell lung cancer(NSCLC)ranked first.Chemotherapy as the first choice for advanced NSCLC,its efficacy has entered the plateau,the median progression-free survival(PFS)is 4 to 8 months,the 1-year survival rate and 2-year survival rate are about 30%and 10%,respectively.With the advancement of precision medicine,the development of molecular biotechnology and the discovery of driving genes,more and more targeted drugs are being used in patients with gene-sensitive mutations in advanced NSCLC.Epidermal growth factor receptor(EGFR)is the most common driver gene.The mutation rate in NSCLC is19%~48%.The mutation types are mostly 19 exon deletion and 21 exon L858R mutation.The emergence of EGFR tyrosine kinase inhibitors(EGFR-TKIs)has benefited patients of advanced NSCLC,with a median PFS of 9 to 12 months and a low toxic side effects.As early as 2013,It has been approved for first-line treatment of advanced NSCLC with EGFR-sensitive mutations.However,in actual clinical applications,there is a significant difference between progression-free survival(PFS)and overall survival(OS)in patients with advanced NSCLC who are treated with EGFR-TKIs.The reason for the difference is unclear.This study compared the clinical features of patients with EGFR single-gene mutations and multi-gene coexisting mutations in advanced NSCLC,and analyze the efficacy with EGFR-TKIs.It will help us to understand the significance of multi-gene coexisting mutations in prognosis and to predict the efficacy of targeted therapy for patients with advanced NSCLC.Then providing a theoretical basis for the choice of targeted drug combination strategiesMethods:A total of 141 patients with advanced NSCLC who were treated with EGFR-TKIs and were identified by a new generation of genetic detection technology(NGS)in our hospital from January 2016 to January 2019.Clinical data of the group(including age,gender,smoking history,family history of cancer,primary site,clinical stage,pathological type,lymph node metastasis,distant metastasis,ECOG score,EGFR mutation type,EGFR targeted drug,post-treatment resistance the drug status,the type and distribution of coexisting mutant genes.According to the coexisting genes,patients were classified into EGFR single gene mutation group and EGFR multi-gene coexisting mutation group,then were followed up regularly.The clinical data of the enrolled patients were analyzed,and the IBM SPSS22.0 statistical software was used for data processing and statistical analysis.To compare the clinical characteristics and analyze the PFS and OS after EGFR-TKIs of ttwo groups,with death as the endpoint.The X~2 test was used to analyze the sex,age,primary site,pathological type,clinical stage,lymph node metastasis,distant metastasis,smoking history,family history of tumor,ECOG score,EGFR mutation type,EGFR-TKIs.Differences in treatment,post-treatment resistance,and efficacy evaluation.The mutated gene of the EGFR multi-gene coexisting mutation group were processed by R language to draw a heatmap to visualize the gene distribution.Survival analysis was performed on the two groups by Kaplan-Meier curve,log-rank for univariate analysis,cox regression model for multivariate analysis,and further analysis of univariate and different coexisting gene numbers in patients with EGFR multigene coexisting mutations.P<0.05 was considered statistically significant.Result:1.A total of 141 patients with EGFR-sensitive mutations in advanced non-small cell lung cancer were enrolled in the study.Among them,101 patients were in the EGFR single-gene mutation group and 40 patients in the EGFR multi-gene coexisting mutation group.The two groups were more common in women,age?60 years,no smoking history,no tumor family history of cancer,adenocarcinoma,right lung,stage IV,lymph node metastasis,single distant metastasis,and ECOG score of 0 to 2 points.Among the EGFR mutation types,the EGFR single gene mutation group had more exons 19 deletion,and the EGFR polygene mutation group had more mutations in the21 exon L858R,but these clinical features were not statistically different between the two groups(P>0.05).2.TP53 is the most common coexisting gene in late NSCLC patients with EGFR multi-gene coexisting mutation group,accounting for about 50%.The second most common germline gene mutations are BIM(10%)and PIK3CA(10%).3.Single factor analysis found that the family history and clinical stage of the tumor were EGFR-sensitive mutations in patients with advanced NSCLC.The prognostic factors of PFS were poor.The clinical stage was the poor prognosis of OS.Multi-factor analysis found that multi-gene coexisting mutations affect PFS and patients with advanced NSCLC in EGFR-sensitive mutations.OS independent prognostic factors.4.The objective response rate(ORR)of the two groups of patients after EGFR-TKIs targeted therapy showed that the EGFR multigene coexisting mutation group was slightly higher than the EGFR single gene mutation group(45%vs 31.7%),but there was no statistical difference(P=0.136).The median PFS of the EGFR single gene mutation group was superior to the EGFR multigene coexistence mutation group(PFS was 12 months vs 7 months,P=0.001).The median OS of the EGFR single gene mutation group was longer than that of the EGFR multiple gene coexistence mutation group(26 months vs 21 months),and the difference was not statistically significant(P=0.284).5.In patients with EGFR multi-gene coexisting mutations,PFS with family history of cancer is shorter(5 months vs 10 months,P=0.001);when the number of EGFR coexisting mutations is 1,2,or more,the PFS were 9 months,8 months,and 5 months,respectively.There was no significant difference between the three groups(P=0.088).However,as the number of coexisting genes increases,the PFS time is gradually shortened.Conclusion:1.There were no significant differences in gender,age,smoking history,family history of tumor,ECOG score,lymph node metastasis,pathological type,and type of EGFR mutation in patients with advanced NSCLC who had EGFR single gene mutation and EGFR multiple gene coexisting mutation.2.TP53 mutation,BIM gene polymorphism deletion,PIK3CA mutation is more common in advanced NSCLC with EGFR multi-gene coexisting mutation.3.PFS in patients with EGFR single gene mutation treated with EGFR-TKIs is superior to EGFR multigene coexisting mutation patients.OS in patients with EGFR multiple gene coexisting mutations may be shorter than patients with EGFR single gene mutations.Patients with a family history of tumors in the group of EGFR multigene coexisting mutations have shorter PFS.4.Multi-gene coexisting mutations are independent prognostic factors affecting the survival of patients with advanced NSCLC with EGFR-sensitive mutations.Family history and clinical stage are the prognostic factors of PFS,and clinical stage is the prognostic factor of OS.