The Relationship Between KRAS And TP53 Mutation Status And Chemotherapy Efficacy Of EGFR And ALK-negative Non-small Cell Lung Cancer

Background:The incidence of lung cancer ranks first in the world,and the mortality rate is increasing year by year.The KRAS and TP53 genes are common mutant genes in NSCLC.In non-small cell lung cancer,10%-30%have KRAS mutations,KRAS mutation rate in lung adenocarcinoma is about 25%,and KRAS gene mutation rate in squamous cell carcinoma is about 5%.The TP53 gene is mutated in approximately 50%of non-small cell lung cancer(NSCLC)and approximately 90%of small cell lung cancer(SCLC).The current main treatments for lung cancer include chemotherapy,radiotherapy,targeted therapy,and immunotherapy.With TKI-targeted drug therapy widely used in NSCLC patients,the progression-free survival(PFS)is significantly longer than chemotherapy alone,but for KRAS.There are currently no effective targeted drug therapies for TP53 mutations.Most studies have shown that the combination of KRAS and TP53 mutations is associated with TKI resistance,but there are few reports on the effects of these two gene mutations on the prognosis of chemotherapy in patients with NSCLC.Several meta-analyses and literature reviews in Western countries have reported on KRAS.The relationship between TP53 mutation and chemotherapy prognosis in patients with NSCLC,but the data obtained are contradictory,so the value of TP53 and KRAS mutations in NSCLC chemotherapy remains controversial.There is no large sample of studies on TP53 and KRAS mutations.The location of chemotherapy at different stages of NSCLC was analyzed.Objective:KRAS and TP53 gene mutations are currently challenging and attractive targets for targeted therapy.This study further clarifies the localization of KRAS mutations and TP53 mutations in the prognosis of patients with different stages of NSCLC,in order to more rationally carry KRAS,Individualized treatment and follow-up clinical monitoring and management of patients with TP53 mutation NSCLC should improve the prognosis of cancer patients as much as possible.Methods:This study collected 238 cases of patients with EGFR and ALK-negative non-small cell lung cancer(NSCLC)from LinkDoc’s Hubble Medical Big Data Platform.All patients were treated with chemotherapy,including early postoperative adjuvant chemotherapy,stage III concurrent chemoradiotherapy,Late palliative chemotherapy.We divided all patients into 4 groups according to the state of gene mutation:WT/WT wild group,KRAS mutation group,TP53 mutation group,KRAS/TP53 co-mutation group.Gene detection methods include a second generation sequencing(NGS)detection method and a scorpion probe amplification repression mutation system(ARMS)assay.The clinicopathological features of these four groups of patients were then analyzed,Kaplan-Meier method was used to assess patient survival,and COX regression analysis was used to estimate KRAS and TP53 mutations with overall survival(OS)and disease-free progression(DFS)or no progression.The risk ratio(HR)associated with lifetime(PFS).This paper is based on the statistical software SPSS.V21.0.Results:There were significant differences in smoking history and pathological type distribution among the four groups(p<0.05).Patients with a history of smoking and adenocarcinoma in the KRAS/TP53 co-mutation group had the highest proportion,while the WT/WT wild group had the lowest proportion..Smoking history,tumor stage,KRAS,and TP53 gene mutation status were closely related to OS in COX univariate and multivariate analysis.There was no significant difference in DFS between the WT/WT group and the other groups in patients receiving early postoperative adjuvant chemotherapy(KRAS:HR 1.49,95%CI[0.77-2.78],p=0.27;TP53:1.37,95%CI[0.84-2.14]p=0.26;KRAS/TP53:HR1.42,95%CI[0.71-3.14],p=0.32;median DFS in WT/WT group was 14 months,95%CI[6.7-38]vs KRAS Group 12.8 months,95%CI[4.9-27]vs TP53 December,95%CI[4.1-36]vs KRAS/TP53 group November,95%CI[3.2-27.8]).However,the WT/WT group was longer than the other three groups(KRAS:HR 3.44,95%CI[1.28-9.21],p=0.017;TP53:4.36,95%CI[1.86-10.15],p=0.0068;KRAS/TP53:HR 2.13,95%CI[0.64-7.28],p=0.026;3-year OS survival rate in the WT/WT group was 69%vs 30%in the KRAS group,34%in the TP53 group,and 39%in the KRAS/TP53 group.<0.05;median OS in WT/WT group was 38 months,95%CI[9.4-53]vs KRAS group in 26 months,95%CI[5.1-46.8]vs TP53 group in 20 months,95%CI[6.2-46.3]Vs KRAS/TP53 group in 15 months,95%CI[4.9-47.2]p<0.05).Similarly,in patients with stage Ⅲ concurrent chemoradiotherapy and advanced palliative chemotherapy,there was no significant difference in ORR and PFS between the WT/WT group and other patients(ORR in the WT/WT group was 41%vs 38%in the KRAS group and 43%in the TP53 group).KRAS/TP53 group 30%,p>0.05;KRAS:HR0.86,95%CI[0.44-1.44],p=0.49;TP53:0.91,95%CI[0.56-1.48],p=0.72;KRAS/TP53:HR 0.93,95%CI[0.52-1.66],p=0.77;median PFS in WT/WT group was August,95%CI[3.5-25]vs KRAS group in July,95%CI[2.1-24]Vs TP53 group 7.2 months,95%CI[2.7-20.1]vs KRAS/TP53 group 6.7 months,95%CI[2.3-19.2]P>0.05).Similarly,the WT/WT group was longer than the other three groups(KRAS:HR 1.17,95%CI[0.56-2.58],p=0.043;TP53:1.37,95%CI[0.71-2.67],p=0.037;KRAS/TP53:HR1.33,95%CI[0.67-2.91],p=0.044;WT/WT group 3-year OS survival rate was 44%vs.KRAS group 30%,TP53 group 31%,KRAS/TP53 group 18%The median OS of the WT/WT group was 23 months,95%CI[6.3-50.3]vs KRAS group for 14 months,95%CI[3.2-45]vs TP53 group for 12.4 months,95%CI[3.4-46.1]vs KRAS/TP53 group 11.6 months,95%CI[3.6-37.6]P<0.05).Conclusion:First,patients with lung cancer with a history of smoking are prone to KRAS/TP53 mutations.COX analysis shows that smoking history and tumor stage are independent predictors of chemotherapy efficacy in patients with NSCLC,and advanced NSCLC patients with smoking history have worse chemotherapy efficacy;,KRAS,TP53 gene mutation and early patients receiving postoperative adjuvant chemotherapy or stage Ⅲ patients receiving concurrent chemoradiotherapy,advanced palliative chemotherapy PFS,DFS has no significant effect,but closely related to patient OS,wild-type NSCLC patients with chemotherapy than carrying KRAS The OS of patients with TP53 mutation is longer,suggesting that the presence of double gene co-mutation may be a predictor of poor prognosis in patients with NSCLC.Third,patients with KRAS/TP53 co-gene mutations have shorter PFS and OS than patients with KRAS or TP53 single gene mutations.Trends,there may be a gene"cumulative superposition effect" of chemotherapy efficacy,suggesting that the type and quantity of gene mutations may be one of the important factors affecting the efficacy and prognosis of patients with chemotherapy.