Influence Of TMB And TP53 Gene Mutation On The Efficacy Of Targeted Drugs In Patients With Advanced Lung Cancer Harboring EGFR-sensitive Mutations

ObjectiveTo explore the influence of tumor mutation burden(TMB)and TP53 gene mutation on the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)in patients with advanced non-small cell lung cancer(NSCLC)harboring EGFR-sensitive mutations.MethodWe enrolled 46 patients with advanced NSCLC who were treated with the first-generation EGFR-TKIs in the Affiliated Hospital of Qingdao University from December 2015 to December 2018.Clinical data and genetic test reports(including TMB value and TP53 gene status)of patients were collected.Age,gender,smoking status,ECOG score,pathological type,clinical stage,the type of EGFR mutations,the type of EGFR-TKI,with or without TP53 gene mutation,TMB level we grouped according to certain criteria.Statistical software SPSS 22.0 was used to analyze the relationship between TMB level,TP53 gene mutation and clinicopathological characteristics,as well as the relationship between the two indexes and efficacy of targeted therapies in patients with NSCLC harboring EGFR mutation.Result1.The median progression-free survival(PFS)of 46 patients was 8.2 months.Univariate analysis found that pathological type,TBM level and TP53 mutation were closely related to PFS of patients.Multivariate analysis of Cox proportional hazard model showed that pathological type(P=0.015),TMB level(P <0.000)and TP53(P <0.000)were independent prognostic factors for PFS;Squamous cell carcinoma,high TMB level,TP53 gene mutation are negatively correlated with TKI efficacy;2.The median TMB level of 46 patients was 4.85 mutations /Mb.The proportion of patients with the combination high TMB and TP53 mutation group(60%)was higher than that with the combination of middle/low TMB and TP53 mutation group(46%).There was no statistically significant difference between TMB in patients with TP53 mutation and TMB in patients without TP53 mutation(P = 0.351);It is suggested that TP53 mutation has no significant effect on the prediction of TMB to the efficacy of TKI in patients;3.The patients were divided into high TMB group and middle/low TMB group.Survival analysis showed that the median PFS of the two groups were 6.300(95%CI,5.175-7.425)months and 9.700(95%CI,7.701-11.699)months,respectively,(P<0.0001),and the difference was obvious;patients were divided into mutated-type TP53 group and wild-type TP53 group,survival analysis showed that the median PFS of two groups were7.400(95%CI,6.164-8.636)months and 11.000(95%CI,8.940-13.060)months,respectively,(P<0.0001),and the difference is obvious;4.The patients were divided into 4 groups according to TMB level and TP53 gene status: median PFS of the combination of middle/low TMB and wild-type TP53 group was 13.000(95%CI,12.358-13.642)months,median PFS of the combination of high TMB and wild-type TP53 group was 7.000(95%CI,5.204-8.796)months,median PFS of the combination of middle/low TMB and mutated-typed TP53 group was 8.200(95%CI,7.368-9.032)months,median PFS of the combination of high TMB and mutated-typed TP53 group was 6.300(95%CI,4.773-7.827)months.The median PFS of the of combination of middle/low TMB and wild-type TP53 group was longer than the median PFS of the other three groups.ConclusionFor patients with advanced NSCLC harboring EGFR-sensitive mutation,TMB level and TP53 mutation have predictive effects on targeted efficacy.High TMB level or TP53 mutation suggest that patients with targeted therapy have shorter PFS.Patients with low/meddle TMB levels and wild-type TP53 benefit most from targeted therapy.