Association Between The KRAS Status And The Efficacy Of First-line Chemotherapy In Patients With Advanced Non-small Cell Lung Cancer

Background and purpose So far,the morbidity and mortality of lung cancer in the country is still the first.Studies have shown that near 87% of mortality resulting from lung cancer is associated with smoking.Other factors of lung cancer susceptibility include age,sex,race,radon exposure,occupation and tuberculosis infection history.Tobacco and nitrosamines can initiate carcinogenic processes that cause lung cancer by influencing the ability of DNA damage repair.In addition,the epigenetic mechanism of the tumor will affect the regulation of oncogenes leading to cell proliferation out of control,escape of programmed cell death,infinite replication of high potential,invasion and metastasis of tissue and neovascularization.With the environmental pollution and the increasing number of smokers,lung cancer in the next few years or even decades may still be the first in the aspect of morbidity and mortality of malignant tumors.Therefore,active prevention and regulation of lung cancer is urgent.Non-small cell lung cancer(NSCLC)accounts for about 85% of lung cancer and is further classified into different subtypes including adenocarcinoma(AC),squamous cell carcinoma and large cell carcinoma.However,about 75% of patients with NSCLC have been diagnosed as IIIB or IV,losing the chance of surgical resection of the tumor.Therefore,cytotoxic chemotherapy and molecular targeted therapy have become the main treatment.In the 1980 s,Chemotherapy began to be applied to the clinical and effectively prolong the survival of patients with lung cancer.Before the concepts of targeted therapy,individual treatment is put forward,chemotherapy is the most effective treatment of advanced lung cancer.In the 21 st century,with the rapid development of molecular pathology,people ushered in a new time of targeted therapy and individualized treatment of lung cancer.Compared with chemotherapy,targeted therapy has both advantages and disadvantages.The advantages are that targeted therapy has mild damage to the normal tissue rather than the tumor tissue.Furthermore,the side effects of targeted therapy are low;the disadvantages is that the population benefiting from the treatment is limited to patients with some gene mutations,however,the proportion of these mutations in the patients is not high,that is,not "broad-spectrum treatment." The study also found that the proportion of these drivers in lung cancer patients has a large difference,so far there are still 40% of lung cancer patients can not benefit from targeted therapy.In recent years,lung cancer-driven genes have been identified,including EGFR,KRAS,EML-4-ALK,RET,ROS1,C-MET and the like.Targeted therapeutic agents represented by EGFR tyrosine kinase inhibitors(EGFR-TKIs)have the advantages of low toxicity and specificity,etc.,which are superior to chemotherapy drugs and have achieved remarkable results in advanced lung cancer.However,exploring the new available driver has always been a hot topic.Although the RAS(Rat sarcoma viral oncogene homolog)gene was first discovered about 30 years ago,targeted therapy for RAS gene has been reported to have failed in clinical practice.A large number of meta-analyzes have shown that KRAS wild-type patients have a better prognosis.However,in retrospective analysis,the predictive significance of KRAS gene in NSCLC has been controversial due to the presence of many inconsistent factors(eg,selection bias,the size of sample size and the difference in chemotherapy regimen).The aim of this study is to further explore the relationship between KRAS gene status and first-line chemotherapy efficacy and progression-free survival(PFS)in patients with advanced non-small cell lung cancer,providing further guidance for clinical practice.Data and Methods The 205 advanced NSCLC who had the EGFR and KRAS test from July 10 rd 2014 to December 1th 2016 in the First Affiliated Hospital of Zhengzhou University were enrolled.Subsequently,a retrospective analysis is carried out in these patients whose EGFR mutation status by histopathologically confirmed is negative.Excluding patients with lost follow-up,185 patients are eligible for this study.Tumor staging is according to the seventh edition of lung cancer TNM staging criteria,and efficacy evaluation is according to the solid tumor efficacy evaluation criteria 1.1(RECIST 1.1)Methods 1.KRAS test method KRAS gene mutation detection is performed by Amplification Blocking Mutation System(ARMS)or direct sequencing.Six mutations of the 12 th and 13 th codons of the KRAS gene are detected,including p.G12 C,p.G12 D,p.G12 V,p.G12 R,p.G12 A,p.G13 D 2.Inclusion criteria(1)All patients agree to genetic testing voluntarily,and sign informed consent before the test;(2)Patients were confirmed as phase III and IV EGFR negative NSCLC according to the seventh edition of lung cancer TNM staging criteria,and had received at least one cycle platinum-based first-line combination of chemotherapy;(3)There are at least one lesion which can be assessed according to the solid tumor efficacy evaluation criteria 1.1(RECIST 1.1);(4)American Eastern Cancer Cooperative Group(ECOG)PS(Performance Status)are 0-1 score;(5)Before and after treatment all patients were carried out CT test,2 cycles of chemotherapy for each evaluation;(6)Palliative radiotherapy is allowed during chemotherapy.3 Evaluation Method The efficacy evaluation is divided into complete remission(CR),partial remission(PR),disease stability(SD)and disease progression(PD)according to the standard of solid tumor efficacy evaluation(RECIST 1.1).Objective response rate(ORR)is defined as the proportion of CR plus PR.Disease control rate(DCR)is defined as the proportion of CR plus PR plus SD.The primary end point is PFS,PFS is defined as the time of the first chemotherapeutic drug to the first recorded PD time or death time.The deadline of follow-up is December 31 th 2016.Patients who have no progress or death within the follow-up date will be calculated according to the date of the last tumor evaluation.4.Statistical Method Apply SPSS 17.0 statistical software for data analysis.The relationship among KRAS gene status,clinicopathological features and the efficacy of chemotherapy is analyzed by using ?2 test or Fisher's test.Survival analysis is performed by using the Kaplan-Meier method and tested by the Log-Rank method.Multivariate analysis of PFS is performed by using Cox regression method.All statistical tests are bilateral probabilistic test,the test level ? = 0.05,P value less than 0.05 is statistically significant.Results 1.KRAS gene mutation Of the 185 cases of non small cell lung cancer,44 cases(23.8%)are found to have KRAS mutation The range of age is 25 to 75,and the median age is 61.5;while 141 cases(76.2%)are founded KRAS wild type mutation,the range of age is 21 to 80,and the median age is 60.The mutation status of KRAS gene are not related to age,sex,smoking history,tumor pathological type and clinical stage.2.Relationship between KRAS mutation state and ORR,DCR 185 patients have measurable lesions.Among them,2 cases(1.4%)are CR,47 cases(37.5%)are PR,66 cases(50.0%)are SD,70 cases(11.1%)are PD,ORR is 26.5%,DCR is 62.2%.In the patients of KRAS wild type,1 case is CR,33 cases are PR,56 cases are SD and 51 cases are PD,ORR is 24.1%,DCR is 63.8%.In the patients of KRAS mutation,1 case is CR,14 cases are PR,10 cases are SD and 19 cases are PD,ORR is 34.1%,DCR is 56.8%.In the male of pemetrexed combination chemotherapy group,1 case is CR,11 cases are PR,7 cases are SD and 4 cases are PD;while in the female,2 cases are PR,3 cases are SD,11 cases are PD.ORR in the male is 52.2%,Which is significantly higher than that in the female(12.5%),the difference is statistically significant,?2 = 6.454,P = 0.011;DCR in the male of pemetrexed combination chemotherapy group is 82.6%,significantly higher than that in the female(31.2%),the difference is statistically significant,?2 = 10.516,P = 0.001.The DCR in KRAS wild type patients is 63.6%,which is slightly higher than that of mutant patients(56.8%),but the difference is not statistically significant,?2 = 0.648,P = 0.421.3.The relationship between the therapeutic efficacy and KRAS mutant subtypes The result shows that there are 16 cases of KRAS G12 D mutation,whose ORR is 37.5%,DCR is 56.3%;10 cases have G12 A mutation,ORR is 50.0%,DCR is 70.0%;7 cases have G12 C mutation,ORR is 14.3%;DCR is 42.9%;6 cases have G12 V mutation,ORR is 33.3%,DCR is 66.7%;4 cases have G12 R mutation,ORR is 0,DCR is 25.0%;1 case has G13 D mutation,ORR is 0,DCR is 100.0%.There are no significant differences in the ORR and DCR results of the mutant subtypes,the mean values of the ORR and DCR are 8.051 and 4.331,respectively,and the P values are 0.153 and 0.503,respectively.The type of KRAS mutation is independent of the therapeutic efficacy.4.The relationship between KRAS mutation status and its mutant subtype,PFS Univariate analysis shows that PFS for KRAS wild type patients is 4.3 months,which is longer than that of KRAS mutations(3.7 months),?2= 21.982,P <0.01.There is no significant difference in PFS among G12 C,G12D,G12 V,G12R,G12 A and G13 D,?2= 5.110,P = 0.403.Multivariate analysis of COX regression showes that KRAS gene mutation is a negative prognostic factor for PFS of first-line chemotherapy in patients with advanced NSCLC,HR = 2.152,95% CI: 1.513-3.062,P <0.01.CONCLUSION1.KRAS mutation is a negative prognostic factor for PFS of first-line chemotherapy in patients with advanced NSCLC 2.Male patients with KRAS mutations respond better to pemetrexed-based chemotherapy.