Individualized Therapy For NSCLC Patients Based On Combined Detection Of Four Biomarkers

Research background:Lung cancer is still the leading cause of morbidity and mortalityin theworldwide. NSCLC accountsfor80to85percent. More than70percent of patientswith lung cancer are diagnosed with advanced(stage IIIB-IV) NSCLC,following apoor prognosis. These patients can only receive medical treatment,such aschemotherapy, targeted therapy and others. Although certain subgroup of patientsobtained a better outcome with the advancement of medical science, the totaltherapeutic efficacy is still not optimistic. Traditional treatment strategies, forexample chemotherapy, are mainly based on the same clinical characteristics, suchas pathology and stage. Therefore, there is no deep sense to think about individualtherapy and is unlikely to bring a fundamental change for NSCLC. The ORR is onlyabout30percent and median PFS is8to10months, with a survival rate at one yearof about30percent[1]. In recent years, with the development of cancer genomics andproteomics, the difference of certain genes mutation or expression is found to beclosely related to the disease occurrence, development, treatment, and prognosis forNSCLC.Studies have shown that EGFR, KRAS, ERCC1, and RRM1genes mutationor expression are important and potential basis for guidance of personal therapy forNSCLC patients. Through the four specific molecular biomarkers screeningmentioned above,the NSCLC patients,efficacy to targeted therapy and chemotherapyis significantly higher than the unscreening group[2-5]. In order to assess whether thefour biomarkers can be used to predict efficacy of targeted therapy or chemotherapyfor the advanced NSCLC patients in Southwestern China,we carried out this study.Objective:To establish and evaluate the individualized treatment strategy for advancedNSCLC patients in Southwestern China based on the combined detection of EGFR,KRAS, ERCC1, and RRM1gene mutation or expression status. Methods:1. The chemotherapy efficacy of239advanced NSCLC with different thirdgeneration drugs plus platinum treatments recruited in Xinqiao Hospital, ThirdMilitary Medical University, from2011.1to2012.12were retrospectively reviewed.The index of curative effect included ORR, DCR and PFS.2. The EGFR mutations of252patients with NSCLC confirmed pathologicallywere determined by ARMS. Meantime, the KRAS mutations of47patients were alsodetermined. Personal therapy was formulated based on themutation of EGFR andKRAS gene.Patients with mutations (not the mutation related to drug resistance) ofEGFR gene received targeted therapy with EGFR-TKIs. On the contrary, thePatients with KRAS mutation did not receive EGFR-TKIs. The associations betweenEGFR and KRAS mutation and the patientss’ clinical characteristics and curativeeffect were analyzedusing chi-square test.3. The ERCC1and RRM1gene expression level of67patients with NSCLCconfirmed pathologically were determined by Q-PCR.All patients receivedplatinum-based double medicine regimen.The associations between ERCC1andRRM1gene expression and the patients’ clinical characteristics and curative effectwere analyzed usingchi-square test.Results:1. The retrospectively analysis of the treatmentefficacyof239cases withadvanced NSCLCpatients who received platinum-based double medicine regimentshowed thatthe ORR and DCR of patients with Paclitaxel plus Platinum,Gemcitabine plus Platinum or Docetaxel plus Platinum regiments were42.5%,43.1%,35.2%(P=0.612)and84.1%,75.0%,74.1%(P=0.198), respectively. The median PFSof three programs was5.6,5.8, and3.2months,respectively(P<0.001).2. Mutation rate of EGFR was43.7%(110/252)among the252NSCLC patients.Mutation rate of EGFR gene was significantly higher in the female (63.8%vs.29.3%male),non-smoker (59.8%vs.25.8%smoker),patients with adenocarcinoma(50.3%vs.14.9%squamous carcinoma), stage IIIB-IV(46.7%vs.26.3%stageIA-IIIA). Among the110patients with EGFR mutations, exon19deletions and exon21L858R mutations were50.9%and42.7%,respectively, which accounting for93.6%of the mutations. Among the47patients of which KRAS mutations were determined, two had mutation and the mutation rate was4.3%.Totally,80patientsreceived targeted therapy with EGFR-TKIs.The ORR and DCR were72.5%and93.8%, respectively. No significantdifferencesin ORRwere found among thesubgroups divided with line of targeted therapy,type of EGFR mutation, mutationabundance, and type of targeted drug.3. The ERCC1and RRM1gene expression of67cases patients were detected.The patients with high, medium-to-high, low to moderate, and low ERCC1geneexpression level accounted for19.4%,34.3%,16.4%, and29.9%, respectively.ERCC1gene expression was positively associated with stage (P=0.014). Thepatients with high, medium-to-high, low to moderate, and low RRM1geneexpression level accounted for49.3%,26.9%,11.9%, and11.9%,respectively. RRM1gene expression level was associated with sex (P=0.018). The efficacy analysis ofplatinum-based double medicine regiment in patientswith different ERCC1geneexpression revealed that there were no significant difference of the ORR and DCRamong subgroups of patients with high, medium-to-high, low to moderate, and lowERCC1gene expression (ORR:46.2%,39.1%,45.5%and45.0%; P=0.971) and(DCR:92.3%,87.0%,90.9%and75.0%;P=0.587). The median PFS of patients withhigh plus medium-to-high and that of patients with low to moderate plus low ERCC1gene expression level was5.0and5.3months (P=0.507). Due to the limited cases(n=9) who received Gemcitabine, the relationshipbetween RRM1gene expressionandGemcitabine outcomes was not analyzed.Conclusion:1. The three platinum-basedchemotherapy regiments all showeda good efficacy.The ORR and DCR were similar.The median PFS of patients with Paclitaxel plusPlatinum and Gemcitabine plus Platinum were significantly longer than that ofDocetaxel plus Platinum.2. EGFR mutations occurred more frequently in female, non-smoker, andpatients with adenocarcinoma in the southwest Chinese. Of the EGFR, mutations atexon19and21were most common, accounting for93.6%. EGFR-TKIs havedemonstrated dramatic efficacy for the patients with activating EGFR mutation.EGFR mutation was the most important predictor biomarker for EGFR-TKIs.3. ERCC1gene was not an ideal molecular biomarker to predict the efficacy of platinum.