Correlation Between KRAS Mutant Subtypes And First-Line Treatment Efficacy And Prognosis In Advanced Non-Small Cell Lung Cancer

Objective: The association between KRAS mutation and the risk of disease progression and death in advanced non-small cell lung cancer is still controversial according to current studies,and the response of different KRAS mutation subtypes to first-line treatment may be different.The purpose of this study is to provide further data and provide evidence-based medical evidence for clinical treatment strategy.Methods: We collected the medical records of advanced NSCLC patients with KRAS mutation status in the Department of Respiratory Oncology,Guangxi Medical University Affiliated Tumor Hospital from January 2010 to September2020,including information of sex,age,BMI,clinical stage,ECOG PS,smoking status,distant metastases,histological classification,KRAS mutation status,biochemical indicators before treatment and first-line treatment.At the same time,we obtained the survival data of the patients through follow-up.According to the status of KRAS mutation,patients were divided into two groups: mutant group and wild type group.The association between covariates and KRAS mutations was determined by χ 2 test / Fisher exact probability method.Kaplan-Meier curve was used to describe the survival of patients between groups,and log-rank test was used to compare survival differences.The Cox proportional hazard model was used to evaluate the effects of variables on PFS and OS,and subgroup analysis was used to verify the interaction effect between covariables and KRAS mutation with prognosis.Results: 710 patients with advanced NSCLC were enrolled in this study,including76 patients with KRAS mutation and 634 patients with KRAS wild type.KRAS mutation was closely related to old age,male,smoking,adenocarcinoma,adrenal metastasis and hypoproteinemia.There was no significant difference in the efficacy of first-line therapy between KRAS mutation and negative patients(P=0.491).Accordingly,univariate analysis showed that the association between KRAS mutation status and the risk of disease progression was not significant(HR=1.02,95%CI 0.73-1.42,P=0.9013),and no subtype of KRAS mutation significantly affected the risk of disease progression(P > 0.05),but KRAS mutation(HR=1.47,95%CI 1.07-2.02,P=0.0162),and other rare KRAS mutation subtypes(HR=3.04,95%CI 1.35-6.84,P=0.0072)was significantly associated with a higher risk of death,and the association between KRAS G12V(HR=2.19,95%CI 0.97-4.91,P=0.0579)and death risk had marginally statistical significance.Multivariate analysis showed that after adjusting for potential confounding factors,KRAS and its subtypes were not significantly associated with the risk of disease progression(P > 0.05),KRAS mutation(HR=1.53,95%CI1.10-2.13,P=0.0115),G12V(HR=3.24,95%CI 1.42-7.37,P=0.0052)and other rare mutations(HR=3.72,95%CI 1.62-8.54,P=0.0019)were significantly associated with the risk of death.Multivariate analysis also confirmed that chemotherapy combined with antiangiogenesis or immunotherapy in the KRAS mutation group was significantly associated with the risk of disease progression(vs.pemetrexed regimen HR=0.45,95%CI 0.21-0.97,P = 0.0414;vs.other nonchemotherapy combined antiangiogenesis or immunotherapy regimens HR=0.44,95%CI 0.21-0.91,P=0.0278),and immunotherapy regimens were significantly associated with reduced risk of disease progression(vs.non-immunotherapy regimen HR=0.27 95%CI 0.10-0.71,P=0.0076).However,each regimen did not significantly affect the long-term survival.Survival analysis showed that the median PFS of patients with KRAS mutation was not significantly different from that of patients with KRAS wild type tumor(4.93 months vs.4.87 months,P=0.9007),but there was significant difference in median OS(9.87 months vs.14.97,P=0.0155).Compared with the wild type,the median OS time of G12 V tends to be shorter(9.24 months vs.14.97 months,P=0.0547).The overall survival of other rare KRAS mutations was the worst compared with that of patients with wild type(8.3months vs.14.97 months,P=0.0057).Conclusion: Mutations and their subtypes are not independent negative predictors of PFS,while KRAS mutations,KRASG12 V and other rare mutations are independent risk factors for overall survival.The efficacy of chemotherapy combined with antivascular or immunotherapy in patients with KRAS mutation is better than other non-chemotherapy combined antivascular or immunotherapy regimens,while immunotherapy is superior to non-immunotherapy,and patients with KRAS mutations may even benefit more from chemotherapy combined with antivascular or immunotherapy.Pemetrexed is also an alternative regimen for patients with KRAS mutations.Paclitaxel regimens tended to increase the risk of disease progression in patients with KRAS mutations,but these treatments did not show a difference in overall survival.