| Background and objectiveLung cancer is the leading cause of tumor-related death worldwide.In the past two decades,the survival of non-small cell lung cancer(NSCLC)harboring driver-genes have been significantly improved due to targeted therapy.EGFR is the therapeutic target with the highest mutation frequency,and is involved in regulating cell proliferation,differentiation and invasion.EGFR-TKI is the most widely used,and related research is endless.Among them,the overall survival(OS)of first-line treatment with Osimertinib reaches more than 3 years.Nonetheless,there are still some patients with poor efficacy and prognosis,so it is urgent to seek effective prognostic biomarker.Tumor mutational burden(TMB)refers to the total number of substitution,insertion or deletion mutations per megabase in the exon coding region of tumor genes,which is closely related to the production of neoantigens.TMB is an effective biomarker for screening and predicting the efficacy of NSCLC and pan-tumor immunotherapy populations,but its correlation with prognosis needs to be confirmed by prospective studies.Blood-based TMB(b TMB)is good correlation of tissue-based TMB,and is a predictor of the efficacy of Atezolizumab.The main reason for the poor efficacy of EGFR-positive patients receiving Immune checkpoint inhibitors(ICIis)is the low level of TMB and poor ability to generate neoantigens.However,the relationship between the efficacy of EGFR-TKIs and TMB level has not yet received widespread attention.Our study was conducted to observe the distribution characteristics of TMB in EGFR-mutant NSCLC and to explore the predictive effect of TMB in patients with EGFR-mutant NSCLC receiving EGFR-TKI.Methods1.Patients selectionWe retrospectively selected 153 patients who were diagnosed with advanced NSCLC in the Oncology Department of Shanghai Changzheng Hospital from January 2017 to May 2019,and were eligible for enrollment by TMB measured by Next-generation sequencing(NGS).The clinical data we collected included age,sex,smoking history,ECOG score,number of metastatic organs,EGFR mutations,TP53 mutations and the presence of co-mutations in other genes.The follow-up time ranged from 3 months to 32 months,with a median follow-up time of 17 months.The follow-up deadline was August 15,2019,and the validation set was supplemented in January 2020.This study was approved by the Ethics Committee of Shanghai Long March Hospital.For retrospective studies,patients did not need to sign an informed consent form.2.Statistical methodsWe set up the initial database with Excel2016 and used SPSS 20.0 for data analysis.Logistic regression was used to analyze the factors affecting TMB expression,Kaplan-Meier method was used to draw progress-free survival(PFS),OS survival curves,and Log rank test was used to evaluate the relationship between various factors and patient survival.PFS risk factors use the Cox proportional hazard model.All P values were taken on both sides,and P <0.05 indicated a statistically significant difference.Results1.Gene mutation spectrumIn 153 patients with advanced NSCLC,the EGFR mutation rate was 45.76%,the 21 L858 R mutation rate was 22.22%,and the exon 19 deletion was 18.95%.The mutation rate of TP53 was 64.71%,of which exons 4 to 8 were the most common,accounting for 52.95% of the total mutation rate.2.TMB distributionThe median TMB of EGFR wild type,EGFR mutant,21 L858 R mutation,19 del,and non-classical mutations were 7.10,3.2,3.17,3.96,and 2.04 mutations / Mb,respectively.The median TMB value of EGFR wild type patients was significantly higher than that of EGFR mutant patients(P <0.0001),and the median TMB of 21 L858 R mutant patients(3.17 mutations / Mb)was lower than 19del(3.96 mutations / Mb)(P = 0.5718).The TP53 wild type and mutant TMB were 1.79 and 6.21 mutations / Mb,respectively.The TP53 wild type TMB value was lower than the mutant type(P <0.0001).Co-mutations of EGFR and TP53 were more common in patients with high TMB(P = 0.0095).3.Clinical characteristicsOf the 61 EGFR positive patients,27 were male(44.26%),34 were female(55.74%),the median age was 62 years,31 were ≥62 years old(51.47%),and 13 patients had a history of smoking(21.31 %),48 patients without smoking history(78.69%).20 cases(32.79%)with ECOG score <2 points,41 cases(67.21%)with ECOG score ≥ 2 points.There were 6 cases without organ metastasis(9.84%)and 55 cases with organ metastasis(90.16%).4.Correlation between TMB and EGFR-TKI efficacy and survivalThe disease control rate(DCR)of the middle and low TMB(TMB-Low & Median,TMB-L & M)group was higher than that of the high TMB(TMB-High,TMB-H)group(88% vs.71.43%,P = 0.262);The objective response rate(ORR)of the TMB-L & M group was higher than that of the TMB-H group(32% vs.23.81%,P = 0.2772).The PFS in the TMB-L & M group was longer than that in the TMB-H group(568 days vs.301 days,P = 0.0449),and there was no statistical difference in OS between the two groups(not reaching vs.793 days,P = 0.1236).TMB(P = 0.017)and the number of metastatic organs(P = 0.013)were independent risk factors affecting PFS in patients with EGFR mutant NSCLC.ConclusionIn patients with advanced NSCLC,the TMB value of the EGFR mutant was significantly lower than that of the wild type,and the TMB value of the 21 L858 R mutation was not different from that of the EGFR 19 del.The TMB value of TP53 mutant patients was significantly higher than that of wild type.Co-mutations of EGFR and TP53 are more common in patients with higher TMB.TMB is a predictor of the negative effect of EGFR-TKI in patients with EGFR-positive advanced NSCLC,but it is not an effective prognostic factor for these patients.TMB and the number of metastatic organs are independent risk factors that affect the efficacy of EGFR-TKI.Age,TP53 mutations were positively correlated with TMB values,and EGFR mutations were negatively correlated with TMB.EGFR 21 L858 R mutation and 19 del are the main EGFR mutation subtypes,and TP53 4～8 exons are the main TP53 mutation subtypes. |
