Study On The Effect Monitoring And Prognosis Judgement Of Tumor Mutation Burden On First-line Chemotherapy In Advanced Non-small Cell Lung Cancer

Background and purposeLung cancer is currently the world’s highest incidence of malignant tumors,of which80-85%are non-small cell lung cancer(NSCLC).Because lung cancer patients are often early symptoms are not obvious,most patients are initially diagnosed in the advanced stage,lost the opportunity for surgery.Although the continuous development of targeted therapy and immunotherapy has brought significant improvement to the prognosis of patients with advanced NSCLC lung cancer,only 40-50%of patients with advanced NSCLC with positive driver gene in Asian population are also patients with advanced NSCLC,and most patients with advanced lung cancer cannot receive targeted therapy due to negative driver gene.Similarly,since the expression of Programmed death ligand 1(pd-l1)is less than 50%in more than 2/3 of patients with advanced lung cancer,most of the first-line immunotherapy for advanced lung cancer still requires combination chemotherapy.Therefore,chemotherapy still plays an important role in first-line treatment of NSCLC.Previous clinical studies and real-world clinical practice have found that the efficacy of first-line chemotherapy in advanced NSCLC patients with the same driver gene negative is significantly different,so the search for biomarkers to predict the efficacy of chemotherapy is still a hot topic in the field of lung cancer research.With the clinical application of Next Generation Sequencing(NGS)technology,a number of studies in recent years have confirmed that Tumor Mutation Burden(TMB)has a significant positive correlation with the efficacy of immunotherapy.The higher the TMB,the better the efficacy of immunotherapy may be.In addition to its application in immunotherapy,previous studies have also confirmed that TMB can significantly affect the efficacy of targeted therapy for lung cancer,and TMB can also predict the efficacy of chemotherapy for advanced colon cancer and the time of postoperative recurrence in patients with early lung cancer.However,it has not been reported whether TMB can predict the first-line chemotherapy efficacy in patients with advanced NSCLC with negative driver gene.Therefore,this study intends to explore the correlation between TMB and first-line chemotherapy efficacy in patients with advanced driver gene negative NSCLC,to provide a new marker for the prediction of first-line chemotherapy efficacy and prognosis in patients with advanced driver gene negative NSCLC,and to provide a new perspective for the clinical application of TMB in patients with advanced NSCLC.Objective and method1.Data acquisitionFifty-six patients with driver gene negative and advanced NSCLC with complete TMB data who were admitted to the oncology department of Shanghai changzheng hospital from January 2017 to December 2019 were reviewed and collected.This study was approved by the ethics committee of Shanghai changzheng hospital.Since the study was a retrospective study,it was not necessary for the patients to sign an informed consent.The following clinical information was collected for all patients:1)general information including:gender,age,smoking history,family tumor history,ECOG score of initial diagnosis,etc.2)laboratory examination indicators included:blood routine,liver and kidney function,c-reaction Protein(CRP),d-dimer and tumor marker.3)tumor-related information includes:primary lesion site,pathological typing,TNM staging,presence or absence of craniocerebral metastasis,TMB,TP53 or KRAS gene mutation,etc.4)efficacy evaluation information based on RECIST 1.1 criteria included first-line chemotherapy without Progression Survival(PFS),Overall Response Rate(ORR),Disease Control Rate(DCR),etc.5)the prognostic information included:follow-up time,Survival status,Overall Survival(OS),etc.All subjects were accepted tumor tissue second Generation Sequencing technology to detect and TMB values calculated for each patient,according to the median TMB divided the patients into two groups:low TMB group(TMB<median),high TMB group(TMB median or higher),analysis of TMB and the correlation between clinical features of patients,evaluate TMB and joint TP53 TMB/KRAS gene mutation status in driving the negative patients with advanced NSCLC first-line chemotherapy curative effect and prognosis judgement of value.In terms of the prediction of immunotherapy efficacy of TMB in patients with advanced NSCLC,due to the lack of a unified TMB cut-off value at present,previous studies on checkmate-227 set the TMB cut-off value to be 10 mut/Mb,which is also the value standard of most current TMB related studies.Therefore,this study also adopted the standard cut-off value of 10 mut/Mb to analyze the application value of TMB in efficacy prediction and prognosis judgment.2.Main research objectivesThis study mainly analyzed the correlation between TMB and PFS,ORR,DCR and OS after first-line chemotherapy in patients with driver gene negative advanced NSCLC.3.Statistical analysisThe enumeration data was represented by the number of cases(percentage),the difference between groups was represented by?~2 test,the measurement data was represented by X±S(mean±SEM),the independent sample T test was used on the basis of normal distribution and homogeneity test of variance,and the non-parametric rank sum test was used for non-normal distribution.Spearman correlation analysis was used in the correlation study,the median survival time was calculated by kaplan-meiter method,and the significance test of the survival difference between the two groups was compared by log-rank method.Univariate and multivariate COX regression models were used to analyze the factors affecting the first-line treatment of PFS and OS in advanced NSCLC.All statistical analyses were conducted in SPSS 23.0,and P<0.05 was considered statistically significant.Results1.General clinical data characteristics and distribution of TMB in different clinical characteristicsAmong the 56 enrolled patients,44 were males and 12 were females,aged between 30and 91 years,with an average age of 62.23±12.86 years.Using nonparametric rank and inspection analysis TMB in different gender,age,smoking history,family history,ECOG score,intracranial tumor metastasis and TNM staging,pathological type of distribution,the results show that the TMB distribution in different gender and ECOG score had significant difference(P<0.05),The TMB value of male patients was higher than that of female patients.The TMB value of patients with ECOG2 was higher than that of patients with ECOG1.2.The clinical characteristics and non-driving genetic factors that affect the level of TMBThe median TMB of the 56 patients was 7.14 mut/Mb.Since the distribution of TMB was non-normal,the median value was defined as cut-off value.Cases with TMB<7.14were included in the low TMB group,and cases with TMB≥7.14 were included in the high TMB group.?~2 test was used to analyze the correlation between different clinical characteristics and non-driver gene factors and TMB value.The results showed that the proportion of males in the high TMB group was significantly higher than that in the low TMB group(93.1%vs 63.00%),and the mutation rate of TP53 in the low TMB group was significantly higher than that in the high TMB group(66.67%vs 37.93%),with statistically significant differences(P<0.05).Spearman correlation analysis was used to analyze whether TMB value and TP53 were mutated or not.The results showed that the expression of TMB value and TP53 were negatively correlated(spearman correlation coefficient=-0.266,P<0.05).3.The correlation between MB and first-line chemotherapy in advanced NSCLC patients with negative driver geneIn this study,7.14 mut/Mb and 10 mut/Mb were set as cut-off values to observe the efficacy and prognosis of patients with advanced NSCLC with negative driver gene after receiving first-line chemotherapy in the low-tmb group and the high-tmb group under different cut-off values.The cut-off value was 7.14 mut/Mb,and the results showed that the ORR in the low TMB group and the high TMB group were 22.22%and 27.59%,respectively,with no statistically significant difference(P>0.05).DCR was 77.77%and 58.62%,respectively,the difference was statistically significant(P<0.05).Median disease-free Survival(m PFS)was 3.5 months and 2.3 months,respectively,with statistically significant differences(P<0.05).The results of subcomponent type showed that m PFS in the low TMB group were significantly better than that in the high TMB group in the elderly(≥65 years old),no brain metastasis,and KRAS wild-type population(P<0.05).COX univariate regression analysis showed that in this study,only TMB was significantly correlated with first-line chemotherapy in patients with advanced NSCLC with negative driver gene(P<0.05).A cut-off value of 10 mut/Mb was used to analyze the correlation between TMB and first-line chemotherapy efficacy in patients with advanced NSCLC.The results showed that the ORR,DCR and m PFS of patients in the low-tmb group were better than those in the high-tmb group(26.32%vs 22.22%).73.68%vs 66.67%;3.3 months vs 2.3 months),but there was no statistically significant difference between the two groups(P>0.05).4.Correlation between TMB and prognostic survival in patients with driver gene negative advanced NSCLCIn this part,the correlation between TMB and Median Overall Survival(m OS)of driver gene negative advanced NSCLC was further analyzed.Of the 56 patients with advanced NSCLC,31 patients reached the end of death,and 25 patients did not show death or loss of follow-up.For the whole population,m OS was 11.0 months(95%ci 8.3-17.5).According to the cut-off value of 7.14 mut/Mb,the prognosis of patients in the low TMB group was significantly better than that in the high TMB group(m OS:23.2months vs8.1months,P<0.01).The results of subgroup analysis showed that:in male,no smoking history,no family history of tumor,lung adenocarcinoma,wild-type TP53,KRAS mutation and wild-type population,m OS in the low-tmb group was significantly better than that in the high-tmb group(P<0.05).Further COX univariate regression analysis showed that gender,brain metastasis,TNM stage,ECOG score and TMB were closely related to the prognosis of patients with driver gene negative advanced NSCLC,but COX multivariate regression analysis showed that males and brain metastasis were independent prognostic factors(P<0.05).Similarly,the prognosis of the low-tmb group with a cut-off value of 10 mut/Mb was significantly better than that of the high-tmb group(m OS:17.5 months vs 7.8 months,P<0.01).5.To explore the effect of TMB combined with TP53 or KRAS gene mutation on the prediction and prognosis of first-line chemotherapy in patients with advanced driver gene negative NSCLCAll patients were divided into four groups(low TMB/t53-wt(wild type),low TMB/t53-mt(mutant type),high TMB/t53-wt,and high TMB/t53-mt)based on the mutation status of TP53 and KRAS genes and the level of TMB/t53-mt(cut-off value7.14mut/Mb).Low TMB/kras-wt,low TMB/kras-mt,high TMB/kras-wt,high TMB/kras-mt),and the differences between PFS and OS in the four groups were compared..In terms of PFS,there was no significant statistical difference in m PFS between the four groups,whether TP53 or KRAS(P>0.05).In terms of OS,there were significant differences among the four groups,among which the patients with low TMB/tp53-wt group had the best prognosis,m OS was 31.4 months.Patients in the high TMB/tp53-mt group had the worst prognosis,m OS was 6.7 months,and the difference was statistically significant(P<0.05).Patients in the low TMB/kras-mt group had the best prognosis,m OS was 31.4months.Patients in the high TMB/kras-mt group had the worst prognosis,with m OS at 6.4months,but the difference was not statistically significant(P>0.05).Conclusion1.When patients with advanced NSCLC with negative driver gene received first-line chemotherapy,compared with patients with high TMB,patients with low TMB had higher DCR and longer first-line treatment PFS;TMB can predict the first-line chemotherapy efficacy in advanced NSCLC patients with negative driver gene.2.Compared with patients with high TMB,patients with advanced driver gene negative with low TMB have longer OS,and TMB can be used to determine the prognosis of patients with advanced driver gene negative NSCLC.3.The mutation status of TP53 gene at different TMB levels significantly affected the prognosis of patients.Among them,the wild-type patients with low TMB combined with TP53 had the longest total survival time,while those with high TMB combined with TP53mutation had the shortest total survival time.However,KRAS gene mutation status at different TMB levels did not significantly affect the prognosis of patients.