Integrated Analysis of HER2 Expression and ERBB2 Alterations in Bladder Cancer

Human epidermal growth factor receptor 2 (HER2) has emerged as a potential therapeutic target in bladder cancer (BC), particularly with the advent of next‐generation antibody–drug conjugates (ADCs) like trastuzumab deruxtecan (T‐DXd). However, the complex relationship between HER2 protein expression, genetic status, and clinical outcomes remains incompletely understood. We conducted an integrated multi‐omics analysis of 445 BC cases (306 muscle‐invasive [MIBC] and 139 non‐muscle‐invasive [NMIBC]) from the OMPU‐NCC cohort, a uniform Japanese clinical database. The study utilized whole‐exome sequencing, RNA sequencing, and refined HER2 immunohistochemistry (IHC) scoring. HER2 IHC positivity (1+/2+/3+) was identified in 30.1% of the cohort. An additional 8.5% exhibited faint membrane staining despite being IHC 0, indicating that detectable HER2 membrane staining was present in approximately 38.5% of cases. HER2 IHC scores showed no prognostic value, whereas ERBB2 amplification, detected in 7.8% of cases, was associated with poorer survival and remained an independent adverse prognostic factor in multivariable analysis (HR, 1.76; 95% CI: 1.08–2.87). ERBB2 amplification was accompanied by frequent co‐amplification of genes within the 17q12 amplicon, including GRB7 , MIEN1 , and PGAP3 . Molecular subtyping revealed that ERBB2 amplification was enriched in the Luminal Unstable (LumU) subtype. In contrast, detectable HER2 membrane staining significantly correlated with high NECTIN4 expression, indicating an overlap between tumors expressing these two ADC targets. HER2 protein expression and ERBB2 amplification represent distinct features of BC. Their integrated assessment may improve molecular stratification and guide future biomarker‐driven studies.