Disease stage-dependent expression of ADC-related biomarkers in urothelial carcinoma.

BACKGROUND: Biomarker-driven therapies have expanded treatment options for advanced urothelial carcinoma (UC), making reliable assessment of therapeutic targets increasingly important for patient selection and treatment sequencing. The aim of this study was to evaluate the expression of clinically relevant biomarkers [Trop2, HER2/neu, Nectin-4, and programmed death-ligand 1 (PD-L1)] across normal urothelium (NT), primary tumors (PT), and lymph node metastases (LNM) in UC, and to explore their potential implications for biomarker-guided therapy. METHODS: Tissue samples from PT (n=157), NT (n=69), and LNM (n=51) were analyzed by immunohistochemistry using established scoring systems [combined positive score (CPS), H-score, immunohistochemical (IHC) score]. Statistical analyses included paired comparisons, correlation analyses, and survival analyses with Kaplan-Meier, and Cox regression. RESULTS: PD-L1 expression was overall low but significantly higher in PT and LNM compared to NT (PT: P=0.001; LNM: P<0.001). Nectin-4 showed low to moderate membranous expression without significant differences across tissue types (P=0.68) and no prognostic impact. Trop2 expression was significantly higher in NT compared to PT and LNM (P<0.001) and was not associated with survival. HER2/neu expression was significantly increased in LNM compared to PT and NT (P<0.01), and was associated with advanced nodal and metastatic stage. No significant co-expression patterns were observed among the four biomarkers. CONCLUSIONS: PD-L1, Nectin-4, Trop2, and HER2/neu show heterogeneous and largely independent expression across disease stages in UC, supporting individualized biomarker assessment and highlighting the potential relevance of metastatic tissue sampling for therapy guidance.