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.
Clinical genitourinary cancer. 2026 May 18 [Epub ahead of print]
Emanuele Crupi, Antonio Cigliola, Chiara Mercinelli, Michela Piacentini, Debora Serafin, Brigida A Maiorano, Andrea Necchi
Vita-Salute "San Raffaele" University Hospital, Milan, Italy; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: ., Vita-Salute "San Raffaele" University Hospital, Milan, Italy; Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele Hospital, Milan, Italy., Vita-Salute "San Raffaele" University Hospital, Milan, Italy., Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele Hospital, Milan, Italy., Vita-Salute "San Raffaele" University Hospital, Milan, Italy; Department of Medical Oncology, Comprehensive Cancer Center, IRCCS San Raffaele Hospital, Milan, Italy. Electronic address: .