Relationship Between Targeted Therapy-related Driver Gene Mutation And Clinicopathological Characteristics In Non-small Cell Lung Cancer

Background: Lung cancer is one of the most common and life-threatening cancer type in most countries globally.During the past several decades,the prevalence and mortality of lung cancer have increased dramatically,which has become one of the most important cause of cancer-related death in China.According to national cancer statistics,about 0.871 million new cases of lung cancer and 0.767 million deaths are expected in 2022,both of which ranked the top of all malignant tumors.In addition,in many areas of China,due to the limited medical and economic conditions,many patients with lung cancer were found to be in advanced stages when they were first diagnosed.In the past,chemotherapy and local radiotherapy were the mainstay treatments for patients with advanced lung cancer.With the development and progress of tumor molecular genetics,many oncogenic and tumor suppressor genes of lung cancer have been discovered.Researchers have developed many specific targeted drugs for these driving genes,which introduced new ways for the treatment of lung cancer.Non-small cell lung cancer(NSCLC)is the most common type of cancer in China,and is also the focus of molecular pathology research.Targeted therapy has been used to treat NSCLC for 20 years.Due to the specificity of targeted drugs,they are only applicable to patients with specific molecular genetic characteristics.NSCLC is mainly driven by genes such as EGFR,ALK and ROS1,and many studies have been conducted on their relationships with NSCLC tumor type,size,differentiation and lymph node metastasis.However,there are relatively limited number of literatures that comprehensively study the genetic variations,pathological characteristics,demographic characteristics and clinical treatment effects of these driving genes.Objective: The aim of this study was to investigate the prevalence of driving genetic variations related to the sensitivity or drug resistance of NSCLC targeted therapy,including variations in EGFR,ALK,ROS1,RET,KRAS,NRAS,BRAF,HER2,PI3 KCA,and MET.We also aimed to explore the relationship between these genetic variations and the pathological characteristics of NSCLC patients,as well as their correlation with the therapeutic effects of targeted drugs,so as to shed more light on the personalized treatment of NSCLC.Methods: According to the inclusion criteria,tumor tissues of 404 Sichuan NSCLC patients who visited Sichuan Provincial People’s Hospital from January2016 to March 2020 were collected.ARMS-PCR(Amplification Refractory Mutation System PCR)mutation detection kit was used to detect the genetic variations related to targeted therapy in NSCLC samples.SPSS was used to analyze the prevalence of genetic variations and their correlation with pathological and clinical characteristics.Results: 1.Genetic variation results: The genetic variation rates of EGFR,ALK,ROS1,RET,KRAS,NRAS,BRAF,HER2,PI3 KCA and MET genes in 404 cases of NSCLC were 52.5%,4.5%,2.0%,1.2%,8.9%,0.2%,1.2%,3.5%,1.0% and 1.5%,respectively.Among them,4 cases of PI3 KCA H1047R/E545 K mutations were all from surgical patient samples,and the other 9 genes showed no difference in the genetic variation rates between surgical and biopsy samples(P>0.05).2.Analysis of genetic variation and clinicopathological characteristics showed that EGFR exon 19 deletion and exon 21 L858 R mutation were more common in female patients and adenocarcinoma(P<0.05).The mutation rate of KRAS gene was higher in male patients and smokers(P<0.05).Tumor grade was correlated with age,gender,smoking,and alcohol consumption(P<0.05).3.Analysis of driving genetic variation and clinical prognosis: 105 of the404 patients died,and the rest 299 patients were alive or lost of follow-up.Follow-up results showed that 93 patients explicitly used targeted drugs,83 of which were accompanied by positive gene variations,and the effective rate of targeted drugs was 92.77%(77/83).Kaplan-Meier survival curve was used to analyze the relationship between driving genetic variations and overall survival.Positivity in ALK gene fusion,NRAS and BRAF mutations were found to be significantly correlated with overall survival(P<0.05).No significant correlation was found between overall survival and genetic variations in EGFR,KRAS,ROS1,RET,HER2,PI3 KC and MET(P>0.05).There were no correlations found between overall survival and the pathological characteristics of patients,such as gender,age,histological classification and clinical stage(P<0.05).Correlation was found between overall survival and smoking and alcohol consumption(P<0.05).A multivariate COX analysis showed that the survival time of patients with EGFR L858 R mutation was significantly higher than that of patients without mutation(P<0.05).Conclusions: 1.Among the driver genes related to targeted therapy in NSCLC,EGFR,KRAS,HER2 mutations and ALK fusion are more common.2.Small biopsy samples from NSCLC patients can also be used for multi-gene and multi-locus detection.3.EGFR L858 R mutation may be an independent prognostic factor for NSCLC.