Correlation Study Between Gene Polymorphism Of Thymidylate Synthase(TYMS) In Peripheral Blood And Efficiency On Pemetrexed-containing Treatment In Advanced Adenocarcinoma Lung Cancer

Objective:Pemetrexed was permitted by Food and Drug Administration(FDA)as a first-line chemotherapeutic drug to treat malignant mesothelioma in 2004 at the first time.After that,clinical researches found pemetrexed also played important role on adenocarcinoma lung cancer and advanced pancreatic cancer.Mechanismly,pemetrexed,as a multi-targeted drug,shows anti-proliferation function by obviously targeting thymidylate synthase(TS),dihydro folate reductase(DHFR)and glycinamide ribonudeotide formyltrausferase(GARFT).TYMS,genetic form of TS,was proved its gene polymorphism could directly impact pemetrexed efficiency on chemotherapeutic sensibility to malignant tumor.However,that correlation-ship mentioned above remains controversial.By analyzing association between TYMS gene polymorphism in peripheral blood and pemetrexed-containing treatment effects in advanced adenocarcinoma lung cancer,we wanted to find whether TYMS gene polymorphism is a predictive factor for pemetrexed treatment outcome.Meanwhile,the purpose of this clinical study was to assess the impact of clinicopathological parameter on treatment efficacy of pemetrexed and gene polymorphism of TYMS.We desire to perfect the model of individual treatment in advanced adenocarcinoma lung cancer at last.Methods:We collected 56 patients who were confirmed as advanced adenocarcinoma lung cancer(ⅢB-Ⅳ stage)by imaging test and pathology between January 1st,2010 and December 31st,2015 in the First Affiliated Hospital of Dalian Medical University.The gene polymorphism of TYMS was detected by using polymerase chain reaction(PCR)with genomic DNA extracted from peripheral blood with the Blood DNA Extraction Kit(Solarbio,D1800,Bei jing).TYMS polymorphisms were presented on 2%agarose gel with ethidium bromide.We only noticed three main phenotypes,including 2R/2R which produces a 116 bp band on the gel,3R/3R with a 144 bp and 2R/3R with both bands of 116 bp and 144 bp.All 56 patients received pemetrexed-containing treatment,and 3 weeks for one cycle.We evaluated treatment efficacy by imageological examination every two cycles during clinical treatment.After four cycles,we assessed patients’ curative effect by imageological examination every two months.The ending time of follow-up was January 1st,2017.Patients’clinicopathological parameter were recorded,including sex,age,clinical pathological stage,ECOG score,smoking situation and gene polymorphism of TYMS.SPSS20.0 was used for data analysis.Kaplan-Meier curves and log-rank tests were used to compare PFS and OS between different gene polymorphism of TYMS.X2 text was used to analyze correlation between clinicopathological parameter and different TYMS genetypes or DCR.Results:1.Age distribution of the 56 patients was from 32 to 80 years old with a median age of 61 years old.Among 56 patients,there were 32 male and 24 female which included 22 stage IIIB patients and 34 stage IV patients.ECOG score of these patients covered from 0 to 2 scores.In these patients,25 were smoker and 31 were not.During chemotherapy,we evaluated tumor development by using RECIST 1.1 and found no one received CR,19 patients received PR,21 patients received SD,16 patients received PD.In all these patients,DCR was 71.43%.2.According main TYMS 5’ UTR gene polymorphism,our study showed 19 samples were 3R/3R,23 samples were 2R/3R and 14 samples were 2R/2R.3.Our data showed patients sex,age,clinical pathological stage,ECOG score,smoking situation and gene polymorphism had no relationship with TYMS gene polymorphism(P>0.05)and DCR(P>0.05).4.We combined 2R/2R and 2R/3R as one kind of group which was sensitive to pemetrexed.After analysis,our findings revealed DCR in 2R/2R and 2R/3R group was distinctly better than 3R/3R group(P<0.05).Simultaneously,PFS in 2R/2R and 2R/3R group was dramatic longer than 3R/3R group(P<0.001).5.OS in 2R/2R and 2R/3R group was slightly longer than 3R/3R group.However,there was no difference between two groups(P=0.10).Conclusions:1.TYMS gene polymorphism in advanced adenocarcinoma lung cancer showed more 2R/3R and 3R/3R,less 2R/2R.2.Patients with TYMS 2R/2R and 2R/3R predicted higher DCR and longer PFS than patients with 3R/3R genomic phenotype during pemetrexed-contained chemotherapy.3.Compared with 3R/3R genomic phenotype,patients with TYMS 2R/2R and 2R/3R showed slightly high of OS.But there was no significant differents.4.TYMS genomic phenotypes may become a high sensitive clinical predictor for patients treated with pemetrexed-contained chemotherapy.