This distinction is increasingly important as HER2-directed antibody-drug conjugates (ADCs), including trastuzumab deruxtecan and disitamab vedotin, move into routine clinical practice.1,4,5 While these agents have demonstrated meaningful activity in HER2-expressing UC, the biological significance of HER2 expression may differ substantially across variant histologies.
Variant histologies are not simply morphologic footnotes. They often embody distinct molecular programs, aggressive clinical behavior, and differential sensitivity to systemic therapies, yet remain underrepresented in prospective trials.6-8 As a result, biomarker interpretation is frequently extrapolated from conventional UC rather than grounded in subtype-specific evidence. This limitation is particularly relevant for HER2. The strongest and most consistent signal has been observed in micropapillary tumors. In contrast, data for squamous, glandular, sarcomatoid, plasmacytoid, nested, and neuroendocrine histologies remain weaker, more variable, or substantially underpowered.6 This imbalance matters because HER2 expression in mixed or variant tumors may be spatially restricted to specific components, raising practical questions about sampling, assay interpretation, and whether a single tissue block or biopsy can adequately define HER2 status.
With greater HER2-directed therapeutic opportunity comes greater biomarker responsibility: whether HER2 represents the same therapeutic signal across biologically distinct UC histologies remains uncertain.
Future HER2-directed studies in UC should report outcomes by histologic subtype, distinguish pure from mixed histology, and specify which tumor component was tested. Integrating the IHC assay platform with ERBB2 amplification, mutation status, spatial heterogeneity, and co-regulated pathways may help move the field from a single-marker approach toward a composite HER2 biomarker. This is particularly relevant in UC, where HER2 biology intersects with molecular subtype and immune-contexture signals, creating potential opportunities for refined patient selection and rational dual or sequential targeting.
Written by:
- Emanuele Crupi, MD Department of GU Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Andrea Necchi, MD, Department of Medical Oncology, IRCCS San Raffaele University Hospital, Milan, Italy
- Meric-Bernstam, F., Makker, V., Oaknin, A., et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J. Clin. Oncol. 42, 47–58 (2024).
- Raggi, D., Crupi, E., Pederzoli, F., et al. HER2 and urothelial carcinoma: current understanding and future directions. Nat. Rev. Urol. 1–23 (2025) doi:10.1038/s41585-025-01075-x.
- Research, C. for D. E. and. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2 (2024).
- Sheng, X., Wang, L., He, Z., et al. Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 42, 1391–1402 (2024).
- Galsky, M. D. Preliminary Efficacy And Safety Of Disitamab Vedotin With Pembrolizumab In Treatment-Naive HER2-Expressing, Locally Advanced Or Metastatic Urothelial Carcinoma: RC48G001 Cohort C. G. ESMO 2024 Annu. Congr. 2024.
- Crupi, E., Cigliola, A., Mercinelli, C., et al. Targeting HER2 in Urothelial Carcinoma: Why Histologic Subtypes and Divergent Histologies Matter. Clin. Genitourin. Cancer 24, 102583 (2026).
- Netto, G. J., Amin, M. B., Berney, D. M., et al. The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs—Part B: Prostate and Urinary Tract Tumors. Eur. Urol. 82, 469–482 (2022).
- Behzatoğlu, K., Yörükoğlu, K., Demir, H. & Bal, N. Human Epidermal Growth Factor Receptor 2 Overexpression in Micropapillary and Other Variants of Urothelial Carcinoma. Eur. Urol. Focus 4, 399–404 (2018).