The Study On SNP Of Drug Metabolizing Enzyme And Efficacy Of Pemetrexed Combined With Cisplatin In Lung Adenocarcinoma

Background and Objective: Lung cancer is currently the most common malignant tumor in the world,and more than 50% of lung cancer patients are already advanced at the time of initial diagnosis.Non-small cell lung cancer(NSCLC)accounts for approximately 85% of all lung pathological types,of which approximately 40% is lung adenocarcinoma.In patients with advanced lung adenocarcinoma who lack indications for targeted therapy,pemetrexed plus cisplatin is currently the standard first-line chemotherapy regimen.Although the factors such as differentiation degree,clinical stage and medication plan are the same,the differences in sensitivity,prognosis,and adverse reactions of different patients are still large.A large number of studies have shown that this difference is related to Single Nucleotide Polymorphism(SNP)of drug-metabolizing enzymes,and drug-metabolizing enzyme gene polymorphisms have a good predictive effect on patients’ treatment response,prognosis and adverse reactions.However,there is no clear conclusion in the study of the efficacy of pemetrexed combined with cisplatin in the treatment of lung adenocarcinoma.This study selected four sites of CYP3A5,CYP2D6,CYP2C8,and GSTP1,which have high mutation rates in Asian populations and participated in the metabolism of most antitumor drugs,and explored their association with advanced lung adenocarcinoma by testing their SNPs.The relationship between response rate(RR),disease control rate(DCR),Progress Free Survival(PFS),and adverse reactions of Cresazide combined with cisplatin was found to be predictive.Biological markers provide a theoretical basis for individualized treatment of cancer patients.Methods: From January 2016 to January 2017,60 patients with advanced lung adenocarcinoma diagnosed by pathology were enrolled in The Second Affiliated Hospital of Dalian Medical University.The first line received pemetrexed plus cisplatin chemotherapy and was followed up to January 2018.Before chemotherapy,EDTA vacuum anticoagulation tube was used to take 5 ml of peripheral blood from the patient and frozen in a refrigerator at-80°C.SNPs were used to detect CYP3A5,CYP2D6,CYP2C8,and GSTP1 gene SNPs in patients’ peripheral blood.To explore the correlation between pemetrexed and cisplatin in the treatment response,prognosis and adverse reactions of advanced lung adenocarcinoma.SPSS23.0 software was used for statistical analysis,P<0.05 was considered statistically significant.Chi-square test or Fisher’s exact test was used to analyze the correlation between clinicopathological characteristics and chemotherapy remission rate and disease control rate.Logistic regression was used to analyze the correlation between SNP and chemotherapy remission rate,disease control rate,and adverse reactions.Kaplan-Meier analysis of the relationship between SNP and PFS in each site was performed.The survival curve was plotted and Log-rank test was performed.Result:1.The detection rates of selected CYP3A5 rs776746,CYP2D6 rs1065852,CYP2C8 rs1113129 and GSTP1 rs1695 loci were all 100%,and all genotype distributions were in accordance with Hardy-Weinberg genetic balance test(P>0.05).2.Analysis of the clinicopathological characteristics of 60 patients enrolled in the study showed that: gender,age,clinical stage,differentiation,and smoking history were not significantly related to chemotherapy remission rate and disease control rate(P>0.05).3.The disease control rate of wild type patients carrying CYP3A5 rs776746 was better than that of mutant patients,which was 12.874 times more than that of mutant patients(P=0.025).The rate of chemotherapy remission among three genotypes,median PFS and myelosuppression,liver toxicity There was no significant difference in the incidence of gastrointestinal adverse reactions(P>0.05).4.The median PFS of patients carrying the CYP2D6 rs1065852 homozygous mutant genotype was shorter than that of wild-type genotype patients(HR=3.78,P=0.011),chemotherapy remission rate,disease control rate and bone marrow among the three genotypes There was no significant difference in the incidence of inhibition,liver toxicity,and gastrointestinal adverse reactions(P>0.05).5.The incidence of gastrointestinal adverse reactions in patients carrying the CYP2C8 rs1113129 homozygous mutation genotype was only 0.09 times that of wild-type patients(P=0.019),chemotherapy remission rate among each genotype,disease control rate,PFS and myelosuppression,liver There was no significant difference in the incidence of toxicity(P>0.05).6.Chemosensitivity of patients with GSTP1 rs1695 mutation was 4.29-fold higher than that of wild-type patients(P=0.032).The incidence of disease control,PFS and myelosuppression,hepatic toxicity,and gastrointestinal adverse reactions among the three genotypes was not significant.Significant differences(P>0.05).Conclusions:1.The CYP3A5 rs776746 wild type mutant has better disease control rate,and the GSTP1 rs1695 mutant has a significantly increased sensitivity to chemotherapy than the wild type.It is suggested that the SNPs of CYP3A5 rs776746 and GSTP1 rs1695 may serve as biomarkers for predicting the short-term therapeutic response of pemetrexed combined with cisplatin in treatment of lung adenocarcinoma.2.The median PFS of CYP2D6 rs1065852 homozygous mutants was shorter than that of patients carrying wild-type genotypes.It is speculated that the SNP of CYP2D6 rs1065852 may be an independent prognostic factor for the treatment of lung adenocarcinoma with pemetrexed plus cisplatin.3.The incidence of gastrointestinal adverse reactions was significantly lower in the CYP2C8 rs1113129 homozygous mutant than in the wild type,suggesting that the SNP of CYP2C8 rs1113129 may serve as a biomarker for the prediction of gastrointestinal adverse reactions in pemetrexed plus cisplatin in the treatment of lung adenocarcinoma.