Correlation Between HER2 And Clinical Pathological Molecular Typing Of Urothelial Bladder Cancer

Background Urothelial bladder cancer(UBC)is the fifth most common malignant tumor in men worldwide.25% of patients are muscle invasive bladder cancer(MIBC)or have distant metastasis at the initial diagnosis which prognosis is poor.UBC patient are mainly treated by surgery and platinum-based chemotherapy,while no available targeted therapy,the outcome is poor and the recurrence rate is quite high.Human epidermal growth factor receptor 2(HER2)is not expressed or cannot detected in normal urothelial tissues,but it is overexpressed in invasive UBC.The positive rate reported of HER2 is 23%-65.5%..For HER2 overexpressed breast cancer,gastric cancer,and gastroesophageal junction cancer,HER2 targeted therapy combined with chemotherapy has become the standard first-line treatment,it is very likely that advanced UBC patients may benefit from HER2 targeted therapy.Several clinical trials for anti-HER2 therapy have been conducted in advanced UBC,while some clinical trials gained survival benefits,the others have failed.This difference in efficacy may be related to the inherent heterogeneity of UBC.In view of the heterogeneity of UBC,TCGA and other institutions divide UBC into two major pathological types,the luminal and the basal/squamous,whose prognosis and therapeutic significance are rather different,similar to breast cancer.HER2 combined with pathological molecular type may provide a basis for screening UBC patients available for anti-HER2 therapy.This study aimed to investigate the correlation between HER2 and UBC clinical pathological as well as molecular type,and provide a theoretical basis for clinical trials for HER2 targeted therapy in UBC.Methods The paraffin-embedded specimens of fifty invasive UBCs and 20non-invasive UBCs were collected which histopathological diagnosis and grade according to the WHO pathological classification criteria 2016,and clinical staging according to the the urinary urothelial carcinoma TNM staging principle 2009(seventh edition).Immunohistochemistry(IHC)was used to detect the expression of HER2 protein in specimens,and the state of gene amplification was detected by fluorescence in situ hybridization(FISH)for IHC 2+ specimens.Invasive UBC molecular typing was performed by IHC detecting GATA3,CK20,CK14,CK5/6 and Ki67 protein expression.Chi-square test and Fisher exact analysis of Correlation between HER2 and clinicopathological data(sex,age,grade,Ki67,pathological molecular type,tumor maximum diameter,muscle-invasion,vascular invasion,lymph node metastasis and clinical stage).P < 0.05 was statistically significant.Results Of the 50 invasive UBCs,42(84%)were high-grade,8(16%)were low-grade;30(60%)were MIBC,and 20(40%)were NMIBC;Nine patients(18%)has vascular invasion while no invasion of 41 cases(82%);41 cases(82%)were luminal type,9cases(18%)were basal/squamous type;36 cases of Ki67?30%(72%),14 cases of Ki67<30%(28%).The positive rate of HER2 invasive UBC was 44%(22/50),and the non-invasive UBC was found no positive in HER2.HER2 positive was significantly associated with invasive UBC,pathological grade,Ki67?30%,and vascular invasion(P<0.05);There was no significant correlation with muscle invasion,regional lymph node metastasis,TNM stage,tumor maximum diameter,gender and age(P>0.05).the distribution in the two pathological molecular types was also significantly different,and the lumen type was significantly higher than the basal/squamous type(P=0.003).Conclusion HER2 is significantly associated with the invasiveness of invasive high-grade UBC.The combination of HER2 status with molecular typing may be helpful in screening potential UBC patients with HER2 targeted therapies.