The Prognostic And Predictive Role Of KRAS Mutation In NSCLC:A Meta-analysis

Lung cancer is the most common human malignant disease and the leading cause of cancer-related mortality worldwide,as well as in China.Lung cancer could be divided into two categories based on different clinical features(prognosis and therapy):non-small cell lung cancer(NSCLC),which accounts for 85%of all case and is represented by squamous cell carcinoma and adenocarcinoma,and small cell lung cancer(SCLC).Basic treatment methods for SCLC,which is characterized by very poor prognosis,include chemotherapy and radiotherapy.Basic treatment methods for NSCLC include surgical resection,radiotherapy and chemotherapy.Patients diagnosed early stage disease receiving curative surgical resection usually presented relative better prognosis,however,most cases developed advanced disease stage when first diagnosed which are unfit to surgical resection.The treatment efficacy of chemotherapy and radiotherapy comes to a platform stage and lasts for a long time.Thus,the five-year survival rate is no more than 20 percent.Not until the beginning of this century,newly developed targeted-drugs erlotinib and gefitinib,epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),showed remarkable treatment efficacy towards specific type of population,mostly featured Asian ethnic,older age,female,adenocarcinoma and non-smokers,after the failure of first-fine chemotherapy.Therefore,FDA approved EGFR-TKIs for the second or third-line treatment of NCLC in 2004.Follow-up studies confirmed that EGFR-TKIs mainly benefit NSCLC patients harboring sensitive EGFR mutation,mostly exon 19 deletion or exon 21 L585 mutations.In a randomized clinical trial,EGFR-TKIs first-line treatment presented better outcomes compared to first-line chemotherapy for advanced lung adenocarcinoma harboring sensitive EGFR mutation.Hence,the NCCN guideline recommended first line EGFR-TKIs treatment for advanced lung adenocarcinoma with sensitive EGFR mutation.Because of remarkable treatment efficacy and less side effects,molecular targeted therapy turned out to be one of the most important and the most promising treatment method for lung cancer in the last decade.It also initiated a new era of "personalized treatment" for NSCLC.Squamous cell carcinoma and adenocarcinoma could be subdivided into different subtype based on different gene mutation and gene rearrangement.Targeted drugs usually benefit specific subtype of cancer but not the other.Gene testing could predict treatment efficacy of targeted drugs and avoid drug abuse.Altered genes are believed to play key roles in the tumorigenesis.By far,known gene alterations in NSCLC include mutation of EGFR,KRAS,HER2,PIK3CA,BRAF and MET,as well as rearrangement of ALK(anaplasticlymphoma kinase gene),ROS1 and RET,with mutations of EGFR and KRAS occurs mostly.Furthermore,mutations of EGFR and KRAS are generally mutual exclusive in NSCLC.In comparison with EGFR wild-type NSCLC,EGFR mutant NSCLC presents remarkable higher response rate and longer progression free survival(PFS)towards EGFR-TKIs treatment.Further investigation confirmed that EGFR mutant NSCLC also exhibits significant better overall survival(OS)and higher objective response rate(ORR)to platinum based doublet chemotherapy.However,the clinical features of KRAS mutant lung cancer have not clearly understood.Early as 1990s,mutant KRAS has bden described as a predictor for poor prognosis and resistance to EGFR-TKIs and chemotherapy in NSCIC.However,as more and more studies comparing the clinical features of KRAS mutant NSCLC with KRAS wild-type NSCLC,results become confusing.Some researchers argued that KRAS mutational status is not significantly associated with poor prognosis or worse treatment outcomes in NSCLC,especially while EGFR mutant tumors were excluded.Thus,the current articles depicted an objective and overall view of clinical features of KRAS mutant NSCLC by using a meta-analysis methodology based on comprehensive search of relative publications across multi-databases.AIM:To investigate the prognosis and predictive role of KRAS mutation in NSCLC,and to provide guidance and advices to the treatment of NSCLC.METHODS:The identification of potential relevant publications was performed through a systemic search in PubMed,Embase and Web of Science databases using the following keywords "lung cancer","non-small cell lung cancer"or "NSCLC" and "KRAS".The latest search was updated on September 2015.Available publications were thereafter screened by inclusion and exclusion criteria.Two investigators independently screened the useful publications follow the inclusion and exclusion criteria,and extracted the useful data by using a standard data-abstraction form.Disagreements were resolved through discussion with another investigator.Extracted data were then aggregated by meta-analysis methodology using Stata SE software.RESULTS:1.A total of 41 publications with 13,103 KRAS assessable patients were eligible for inclusion in the present analyses.2.KRAS mutation occurs more frequently in lung adenocarcinoma(relative risk,RR=1.16,p=0.016),and in formal or current smokers(RR=1.13,p=0.017),but not in male gender(RR=1.07,p=0.142).Reported gene mutation rate is 18%in all patients,the rate ranged from 4.4%to 24.5%in the Asians and from 6.7%to 47.4%in the Caucasians.3.In unselected NSCLC,KRAS mutation was significantly associated with worse OS(hazard ratio,HR=1.56,95%CI 1.39-1.76)and disease-free survival(DFS)(HR=1.57,95%CI 1.17-2.09)in early stage resected NSCLC,and with inferior outcomes of EGFR-TKIs treatment(RR=0.21 for ORR,95%CI 0.12-0.39;HR=1.46 for PFS,95%CI 1.23-1.74)and chemotherapy(RR=0.66 for ORR,95%CI 0.54-0.81;HR=1.30 for PFS,95%CI 1.14-1.50)in advanced NSCLC.5.When EGFR mutation patients were excluded,KRAS mutation was still significantly associated with worse OS(HR=1.40,95%CI 1.21-1.61)and PFS of EGFR-TKIs(HR=1.35,95%CI 1.11-1.64).Although KRAS mutant patients presented worse DFS(HR=1.33,95%CI=0.97-1.84)and PFS of chemotherapy(HR=1.11,95%Cl 0.95-1.30),and lower ORR to EGFR-TKIs(RR=0.55,95%CI 0.27-1.11)and chemotherapy(RR=0.88,95%CI 0.76-1.02),statistical differences were not met.CONCLUTIONS:KRAS is a weak,but valid predictor for poor prognosis and treatment outcomes in NSCLC.By far,there is no clinical approved effective treatment method for KRAS mutant lung cancer or other tumors.There is a crying need for developing specific treatment method directly towards aberrant Ras signaling.The major contributions of the present study lie in:The current work depicted an overall view of clinical features of KRAS mutant NSCLC by using meta-analysis methodology based on by far the most and the newest relevant publications.Besides,EGFR mutation tumors were excluded to assess the independent role of mutant KRAS.