Clinical Analysis Of The Efficacy And Drug Resistance Of Targeted Therapy For Advanced Non-Small Cell Lung Cancer With EGFR Mutation

Background and Objective: Lung cancer is still one of the most common malignant tumors in our daily life,with a very high mortality rate.Although the discovery of driver genes and the development of targeted drugs have brought significant clinical benefits to a large proportion of patients,the occurrence of drug resistance is inevitable.Therefore,it is very important to observe the efficacy of targeted therapy in the real world and explore the potential mechanism of drug resistance.This study aims to retrospectively analyze the mutation rate of EGFR gene in NSCLC in the real world,analyse the relationship between EGFR mutation and the clinical pathological characteristics,observe the efficacy of targeted therapy and look for prognostic factors.At the same time,to analyse the potential mechanism of EGFR TKI resistance from the clinical perspective,which laid a foundation for further exploration of the mechanism of resistance and development of treatment strategies after drug resistance.Research methods:The general clinical data and genetic testing reports of all patients with pathologically confirmed NSCLC and second-generation sequencing(from Shanghai Baoteng Medical Laboratory)with clear driver gene status who were admitted to the First Affiliated Hospital of Yangtze University/Jingzhou First People’s Hospital from January 2016 to December 2019 were collected,and return visits was conducted.Firstly,the mutation rate of EGFR driver gene in the population and the proportion of EGFR sensitive mutation(19del and L858R)patients in Jingzhou area were analyzed.Then,for patients who clearly met the inclusion and exclusion criteria,the chi-square test was used to analyze the correlation between EGFR mutations and various clinicopathological features.Then,the efficacy of EGFR-sensitive mutation patients who met the inclusion and exclusion criteria and received first-line targeted therapy was observed.Kaplan-Meier survival analysis and Log-rank test were used to analyze the effects of each clinicopathological feature on PFS.Meanwhile,survival curves were ploted and Cox regression model was used to estimate the multivariate associated with PFS.Finally,EGFR co-mutated genes were recorded.Kaplan-Meier survival analysis and Log-rank test were used to compare the differences in PFS between patients with and without co-mutation.Meanwhile,survival curves were drawn and Cox regression model was used to estimate the multivariable factors associated with PFS.Multivariate analysis was carried out for the index P<0.05 in univariate analysis.Results:1.Among the 623 NSCLC patients who underwent genetic testing in Jingzhou region,the mutation rate of EFGR was 39%(240/623),of which 42.5%(102/240)were19del and 43.3%(104/240)were L858 R.The other rare mutations included G719 X,L861Q,S768 I,T790M and compound mutations,which accounted for 14.2%(34/240).2.In 436 patients with advanced NSCLC,EGFR mutation was associated with female(P<0.001),adenocarcinoma(P=0.004),non-smoking(P<0.001),brain metastasis(P=0.037),and CEA higher than the upper limit of normal(P<0.001).3.Among the patients with EGFR-sensitive mutations(19del and L858R)in advanced non-small cell lung cancer who met the inclusion and exclusion criteria,129 patients received first-line targeted therapy,of which 102 were effective and the effective rate was 79%.The m PFS of the total population was 10 months.Among them,gender(P=0.512),age(P=0.930),pathological type(P=0.662),ECOG score(P=0.940),smoking history(P=0.274),bone metastasis(P=0.340),brain metastasis(P=0.466),CEA(P=0.209),CA125(P=0.889),CYFRA21-1(P=0.337),mutation site(P=0.575),and type of targeted drug(P=0.208)were not prognostic factors for PFS.4.In 102 patients with targeted therapy,including 61 patients with TP53mutations(61/102,59.8%),27 patients with PTEN mutation(27/102,26.5%),18 patients lack of RB1(18/102,17.6%),16 patients with PIK3 CA mutation,(16/102,15.7%),9patients with ROS1 fusion,(9/102,8.8%),9 patients with CTNNB1 mutation,(9/102,8.8%),7 patients with RET mutations(7/102,6.9%),7 patients with BRAF mutation(7/102,6.9%),5 patients with T790 M mutation(5/102,4.9%),5 patients with HER2amplification(5/102,4.9%),3 patients with MET amplification(3/102,2.9%),3patients with EGFR amplification(3/102,2.9%),3 patients with ALK fusion(3/102,2.9%),and 2 patients with NRAS mutation(2/102,2.0%).Kaplan-Meier univariate analysis suggested that prior to TKI treatment,combined PIK3 CA mutations(P=0.047),T790 M mutations(P=0.001),HER2 amplification(P=0.032),and Met amplification(P=0.001)were associated with poorer PFS.Further Cox multivariate regression analysis showed that combined PIK3 CA mutation(m PFS 8 months,95%CI,HR 0.548,P=0.04),HER2 amplification(m PFS 7 months,95%CI,HR 0.330,P=0.02),Met amplification(m PFS 3 months,95%CI,HR 0.140,P=0.001)were independent risk factors for PFS.Conclusions:1.EGFR mutations account for 39% of lung cancers in Jingzhou,of which 19 del and L858 R account for 86% of the total mutations.2.Patients who are Female,adenocarcinoma,non-smoking,with brain metastases,and elevated CEA are susceptible to EGFR mutation.3.The effective rate of first-line targeted therapy of advanced NSCLC with EGFR-sensitive mutations was 79%,and the m PFS was 10 months.Gender,age,ECOG score,smoking history,pathological type,presence of bone metastasis,presence of brain metastasis,tumor marker status,mutation site and type of targeted drugs were not prognostic factors for PFS.4.Comutation with PIK3 CA mutation,HER2 amplification and MET amplification before EGFR-TKI treatment were independent risk factors for PFS,which accelerated the occurrence of drug resistance.