Targeting HER2 in Urothelial Carcinoma: Why Histologic Subtypes and Divergent Histologies Matter

HER2 is emerging as a clinically relevant target in urothelial carcinoma (UC), but its biological and therapeutic significance is not uniform across histologic subtypes and divergent histologies. These tumors are characterized by marked clinicopathologic heterogeneity, aggressive behavior, and limited representation in prospective trials, complicating biomarker development. Available data suggest that ERBB2 alterations are enriched in selected subtypes, most consistently in micropapillary UC, whereas plasmacytoid, squamous, sarcomatoid, and glandular histologies generally show lower and more variable rates of HER2 overexpression or amplification. However, interpretation is constrained by small retrospective series, assay discordance, and the absence of standardized HER2 scoring criteria for UC. In the antibody-drug conjugate era, resolving these subtype-specific and methodological uncertainties is essential for refining patient selection and defining the clinical role of HER2-directed therapy across histologic subtypes and divergent histologist.