HER2 overexpression significantly associates with higher grade, progression, and lymph node metastasis in bladder cancerHER2 Overexpression Linked to Higher Risk in Bladder Cancer

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression is an established oncogenic driver and therapeutic target in several malignancies, but its clinical significance in urothelial carcinoma (UC) of the bladder remains controversial due to disease heterogeneity and lack of standardized assessment. OBJECTIVE: To synthesize evidence on the stage-specific associations of HER2 overexpression with clinicopathological features in bladder UC through a systematic review and meta-analysis. METHODS: We conducted a PRISMA-compliant systematic review and meta-analysis, searching PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) up to November 6, 2025. Included studies were retrospective observational cohorts of treatment-naive bladder UC patients with HER2 assessed by immunohistochemistry (IHC). Data on HER2 positivity (various IHC thresholds) stratified by clinicopathological variables were extracted. Random-effects models calculated pooled risk differences (RD) with 95% CI (confidence intervals), stratified by non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive/metastatic bladder cancer (MIBC/mUC). Heterogeneity was assessed via I, and subgroup analyses explored IHC thresholds. RESULTS: 19 studies were included (9 on NMIBC, 10 on MIBC/mUC), comprising a total of 2799 patients (NMIBC: 1751; MIBC/mUC: 1048). In NMIBC, HER2 overexpression was significantly associated with higher T stage (RD: 0.11, 95% CI: 0.08-0.15), higher grade (RD: 0.22, 95% CI: 0.16-0.28), multifocality (RD: 0.10, 95% CI: 0.05-0.15), recurrence (RD: 0.22, 95% CI: 0.10-0.35), and progression (RD: 0.31, 95% CI: 0.23-0.39). In MIBC/mUC, significant association was observed only with lymph node metastasis (RD: 0.11, 95% CI: 0.03-0.19). Associations were consistent across IHC thresholds. CONCLUSIONS: HER2 overexpression exhibits stage-specific patterns, strongly linked to aggressive features and progression risk in NMIBC but primarily to lymphatic spread in MIBC/mUC. These findings provide preliminary evidence supporting HER2 as a stage-specific biomarker, with implications for risk stratification and emerging targeted therapies.