Study On The Prognosis Of Molecular Subtypes Of Invasive Bladder Cancer And The Correlation Between EGFR,FGFR3 And PD-L1 Protein And Molecular Subtyp

BACKGROUND Bladder cancer is the most common malignant tumor in the urinary system,and its incidence is increasing year by year in recent years.According to the depth of tumor invasion,invasive bladder cancer is divided into non-muscular invasive bladder cancer and muscular invasive bladder cancer.There are great differences between them in biological behavior,choice of treatment and prognosis.As invasive bladder cancer is a highly heterogeneous disease,there are great differences in treatment response and prognosis for patients with the same histological type,grade and stage.Therefore,it is necessary to establish a bladder cancer classification system based on comprehensive multivariate analysis in order to achieve the purpose of accurate diagnosis and treatment.With the development of molecular biology and the application of various biological detection techniques,the molecular subtypes of bladder cancer are becoming more and more perfect.Molecular subtypes play important role in elucidating the pathogenesis of bladder cancer,predicting patients’ responsiveness to therapeutic drugs and evaluating prognosis.OBJECTIVE 1.The purpose of our study was to investigate the relationship between molecular subtypes,clinicopathological features and prognosis of invasive bladder cancer.2.To further analyze the relationship between the molecular subtypes of invasive bladder cancer and the efficacy of adjuvant chemotherapy.3.To detect the expression of epidermal growth factor receptor(EGFR),fibroblast growth factor receptor 3(FGFR3)and programmed cell death ligand 1(PD-L1)in invasive bladder cancer,and to analyze the correlation between different subtypes and the above three markers.METHODS 1.A total of 132 cases of invasive bladder cancer diagnosed in the Department of Pathology of Inner Mongolia Medical University from January 2016 to December 2018 were collected,and all of them were urothelial carcinoma.Clinical data of patients were collected by consulting medical records,and the survival status of patients was followed up by consulting medical records and telephone,5 caces were lost to follow-up.Using immunohistochemistry to detect the expression levels of cytokeratin14(CK14)and cytokeratin 20(CK20)in tumor specimens,and invasive bladder cancer was divided into luminal type(CK14-,CK20+),basal type(CK14+,CK20-)and double negative type(CK14-,CK20-).To explore the relationship between different molecular subtypes and clinicopathological features,adjuvant chemotherapy and prognosis.2.The protein expressions of EGFR,FGFR3 and PD-L1 were detected by immunohistochemical method,and the correlation between the expression of three proteins and molecular subtypes was analyzed.RESULTS 1.A total of 122 patients with invasive bladder cancer were enrolled in this study,56(45.9%)were luminal type,43(35.2%)were basal type,and 23(18.9%)were double negative type.2.There was no significant difference among different molecular subtypes in age,sex,tumor size,tumor number,tumor grade,vascular invasion,lymph node metastasis and recurrence(P>0.05).There were significant differences in pathological stage and distant metastasis(P<0.05).3.Kaplan-Meier analysis showed that there were significant differences in over all survival(OS)and disease-free survival(DFS)among patients with different molecular subtypes of bladder cancer(P>0.05).The results of pairwise comparison showed that the OS and DFS of patients with luminal type were better than those of the other two types(P>0.05),but there was no significant difference in OS and DFS between basal type and double negative type(P>0.05).4.Multivariate analysis by Cox proportional hazard regression model showed that age and distant metastasis were independent risk factors for OS(P<0.05).5.According to different treatment methods,122 patients were divided into three groups: radical cystectomy(RC)group,transurethral resection of the bladder tumor(TURBT)group and TURBT plus postoperative adjuvant chemotherapy group.The results of Kaplan-Meier analysis showed that there was no significant difference in OS and DFS among different subtypes of patients receiving different treatments(P>0.05).The paired results showed that the OS of patients with basal tumors who received TURBT plus postoperative adjuvant chemotherapy improved compared with those who received TURBT alone(P<0.05).There was no significant difference in DFS and OS between patients with luminal type and double negative type(P>0.05).6.The expression of EGFR was positively correlated with the expression of basal tumor marker CK14(r=0.186,P<0.05),the expression of PD-L1 was positively correlated with the expression of basal tumor marker CK14(r=0.297,P<0.05),and negatively correlated with the expression of luminal tumor marker CK20(r=-0.251,P<0.05),but there was no correlation between the expression of FGFR3 and the expression of CK14 and CK20(r=0.024,r=0.060,P>0.05).7.EGFR and PD-L1 showed statistically significant differences among different molecular subtypes(P<0.05),that is,basal tumors were highly expressed in EGFR and PD-L1.There was no significant difference in FGFR3 expression among the three molecular subtypes(P>0.05).8.Detecting the survival of patients under different expressions of EGFR,FGFR3,and PD-L1,Kaplan-Meier analysis results show that EGFR,FGFR3 and PD-L1 have no statistical differences in OS and DFS in different expressions(P>0.05).CONCLUSION 1.According to the different expression states of CK14 and CK20,invasive bladder cancer can be divided into luminal type(CK14-,CK20+),basal type(CK14+,CK20-)and double negative type(CK14-,CK20-).2.The prognosis of patients with the three molecular subtypes was different.The luminal type patients had the best prognosis,while the basal type and the double-negative type patients had poor prognosis.3.The sensitivity of the three molecular subtypes to postoperative adjuvant chemotherapy is different,the basal subtypes are more sensitive to postoperative adjuvant chemotherapy than the other two subtypes.4.Compared with the other two subtypes,EGFR and PD-L1 were highly expressed in basal tumor tissues,and the expression of basal marker CK14 was positively correlated with the expression of them,suggesting a potential response to EFGR inhibitors and immune checkpoint inhibitors in this type of patients.