Expression Of CDC34 And PD-L1 In Non-small Cell Lung Cancer With EGFR Mutation And Its Clinical Significance

Background and ObjectiveThe incidence rate of lung cancer is second,and the mortality rate is the highest.85%of them are non-small cell lung cancer(NSCLC),among which epidermal growth factor(EGFR)is the most common driving gene mutation,which mainly includes 19 exon deletion mutations,21 L858R mutations and rare mutations.With the development of gene detection technology and precision medicine,targeted molecular targeted therapy has significantly prolonged the survival time of patients.EGFR tyrosine kinase inhibitors(EGFR-TKIs)are the standard first-line treatment for EGFR mutated NSCLC,including The first generation of Gefitinib,Erlotinib,Icotinib,the second generation of Afatinib,Dacomitinib,and the third generation of Oxitinib,etc.With the update of clinical application data,not all EGFR mutated NSCLC are sensitive to targeted therapy,and acquired drug resistance is inevitable.Effective anti-tumor treatment measures to overcome the resistance of EGFR-TKIs have not been solved.With the advent of the era of immunity,immunotherapy for patients with NSCLC has the characteristics of relatively long-term efficacy and safety tolerance,and has entered a number of guidelines.However,further treatment options are still limited after EGFR-TKIs resistance.At present,PD-L1 expression has become a predictive and prognostic biomarker for immunotherapy of NSCLC.Although the exploration of predictive and prognostic biomarkers such as PD-L1 and TMB in EGFR mutated NSCLC and related immunotherapy schemes are gradually updated,the clear relationship between EGFR mutated NSCLC and PD-L1expression is still unclear,and the effect of immunotherapy needs to be improved.Therefore,exploring the changes of drug resistance and immune microenvironment in EGFR mutant NSCLC will help to overcome the congenital and adaptive drug resistance,improving the relevant treatment measures,and improve the survival benefit of patients.CDC34 is an E2 ubiquitin binding enzyme that controls cell cycle.It can control EGFR protein hydrolysis together with E3 ubiquitin ligase.It is related to EGFR gene mutation driving lung cancer mouse model.It is related to the regulation of p ERK and p Akt signaling pathway and has a common signaling regulation pathway with PD-1/PD-L1 pathway.However,the relationship between CDC34 expression and PD-L1 expression in EGFR mutanted NSCLC is unknown.In this study,the expression of CDC34 and PD-L1 in EGFR mutated NSCLC tissues was detected by immunohistochemical method to explore their correlation and its impact on the prognosis of patients.Materials and Methods49 specimens of tissue wax from surgically resected non-small cell lung cancer patients with EGFR mutant in the Department of Pathology of the Second Affiliated Hospital of Zhengzhou University were selected.The control group consisted of 49normal tissue wax blocks,which are adjacent to the cancer.The expressions of CDC34 and PD-L1 in cancer tissues and adjacent tissues were detected by immunohistochemistry.Spss26.0 software was used for statistical analysis.T test was used for measurement data;frequency/rate andχ2 test was used for count data.Correlation analysis of variables using spearman rank correlation analysis,Kaplan-Meier method was used for survival analysis,log rank test was used for survival rate comparison,and Cox risk model was used for univariate and multivariate analysis to compare prognostic factors.Inspection levelα=0.05Results1.Immunohistochemical staining is shown in Figure 1.CDC34 was mainly expressed in tumor cell membrane and cytoplasm,and PD-L1 was mainly expressed in tumor cell membrane.In 49 cases of cancer tissues,36 cases(73.5%)were positive for CDC34 and 13 cases(26.5%)were negative for CDC34.In corresponding adjacent tissues,7 cases(14.3%)were positive for CDC34 and 42 cases(85.7%)were negative for CDC34,χ~2=34.849,P<0.001.The difference was statistically significant,indicating that the expression of CDC34 in EGFR mutanted NSCLC was significantly higher than that in adjacent tissues.In 49 cases of cancer tissues,15cases(30.6%)were PD-L1 positive and 34 cases(69.4%)were PD-L1 negative.In corresponding adjacent tissues,8 cases(16.3%)were PD-L1 positive and 41 cases(83.7%)were PD-L1 negative,χ~2=4.909,P=0.027.The difference was statistically significant,indicating that the expression of PD-L1 in EGFR mutanted NSCLC was significantly higher than that in adjacent tissues,but it tends to be negative.2.In 49 cases of NSCLC harbouring EGFR mutation,the expression of CDC34had significantly correlated with smoking history(P=0.030)and TNM stage(P=0.043),but had no significantly correlation with age,gender,ECOG score,EGFR mutation type and Ki67(P>0.05);the expression of PD-L1 had significantly correlated with gender(P=0.042)and tumor differentiation(P=0.007),and there was no significant correlation with age,ECOG score,EGFR mutation type,Ki67、tumor TNM stage.3.The correlation between CDC34 expression and PD-L1 expression in EGFR mutanted NSCLC was compared.The results showed that Spearman correlation coefficient r was 0.199,P value was 0.172,there was no significant correlation.4.Univariate analysis showed Tumor TNM stage(HR=1.877,P=0.041),CDC34expression(HR=2.974,P=0.008)and PD-L1 expression(HR=1.616,P=0.043)were the influencing factors of RFS in patients of NSCLC harbouring EGFR mutation,and the difference was statistically significant.Tumor stage(HR=2.284,P=0.017),CDC34 expression(HR=3.381,P=0.001)and PD-L1 expression(HR=2.24,P=0.022)were the influencing factors of OS in patients of NSCLC harbouring EGFR mutation,and the difference was statistically significant.5.Multivariate analysis showed that expression of CDC34(P=0.010)and PD-L1(P=0.006)were independent risk factors for RFS in patients of NSCLC harbouring EGFR mutation,and tumor TNM stage(P=0.008),the expression of CDC34(P=0.005)and PD-L1(P<0.001)were independent risk factors for OS.6.The RFS and OS of patients with double positive expression of CDC34 and PD-L1 were significantly lower than those of patients with double negative expression of CDC34 and PD-L1(p<0.001).Conclusions1.The expression of CDC34 and PD-L1 in tumor tissues of patients with EGFR mutanted NSCLC were significantly higher than those in adjacent tissues.And there was no correlation between the expression of CDC34 and PD-L1.CDC34 expression was correlated with smoking history and tumor TNM stage,but has no correlation with age,gender,ECOG score,EGFR mutation type and Ki67.PD-L1 expression is related to gender and tumor differentiation,but had no association with age,ECOG score,EGFR mutation type,Ki67 and tumor TNM stage.2.In patients with EGFR mutanted NSCLC,the RFS and OS of patients with CDC34 positive expression were shorter than those with negative expression.PD-L1positive expression overlapped with EGFR mutation,and RFS and OS of patients with PD-L1 positive expression were shorter than those with negative expression.The survival of patients with double positive expression of CDC34 and PD-L1 was significantly lower than that of patients with double negative expression.3.CDC34 expression and PD-L1 expression are independent risk factors for RFS in patients with EGFR mutanted NSCLC,and tumor stage,CDC34 expression and PD-L1 expression are independent risk factors for OS in patients with EGFR mutanted NSCLC.double positive expression of CDC34 and PD-L1 are independent risk factors for RFS and OS in patients with EGFR mutanted NSCLC.