Abstract
Human epidermal growth factor receptor 2 (HER2) has emerged as a crucial biomarker across various cancers, shaping therapeutic strategies and prognostic evaluations. In urothelial carcinoma, HER2 positivity rates can reach up to 68% when HER2-low tumours (immunohistochemistry 1+) are included in the analysis. HER2 overexpression and ERBB2 genomic alterations have been linked to advanced disease stages and poor outcomes in urothelial carcinoma. Emerging evidence suggests that HER2-low tumours might be a distinct and actionable subgroup. Accurate and consistent assessment of HER2 status is increasingly vital to identify patients likely to benefit from HER2-targeted therapies, raising interest in refining thresholds for HER2 expression, aiming to predict treatment response. HER2 heterogeneity across stages and histological subtypes complicates its evaluation, with definitions of HER2 positivity differing between clinical trials and treatments. In urothelial carcinoma, HER2-targeted therapies, such as tyrosine kinase inhibitors, monoclonal antibodies and antibody–drug conjugate (ADCs) have been explored. Unlike tyrosine kinase inhibitors and monoclonal antibodies, which act through HER2-related pathways, ADCs use HER2 as a target but achieve efficacy through additional mechanisms, enabling their activity even at low HER2 expression levels. Trastuzumab deruxtecan, a novel anti-HER2 ADC, has received FDA tumour-agnostic approval for unresectable or metastatic HER2+ solid tumours, including urothelial carcinoma, after prior therapies. Interactions between HER2 protein and putative biomarkers such as EGFR, NECTIN4, PDL1 and FGFR3 genomic alterations might influence therapeutic outcomes, offering opportunities for improved patient selection and innovative combination strategies.
Key points
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Human epidermal growth factor receptor 2 (HER2) assessment in urothelial carcinoma is highly inconsistent and heterogeneous across studies. Establishing a standardized, universally accepted HER2 immunohistochemical testing framework is crucial for achieving reliable and reproducible results.
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HER2 positivity in urothelial carcinoma varies considerably by anatomical location, disease stage, histological subtype, molecular classification and between matched primary and metastatic tumours, complicating consistent evaluation and interpretation.
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The prognostic and predictive value of HER2 or ERBB2 status in urothelial carcinoma remains uncertain. Clinical trials of anti-HER2 monoclonal antibodies and small-molecule inhibitors, such as tyrosine kinase inhibitors, have largely produced inconclusive or negative outcomes.
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Promising early data on anti-HER2 antibody–drug conjugates, as observed in other cancers, suggest that their unique mechanism — leveraging HER2 as a docking target independent of its signalling function — could overcome prior therapeutic challenges.
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Encouraging initial results with antibody–drug conjugates in HER2-low and HER2− tumours suggest that HER2 expression levels could be a better predictor of treatment response than traditional positivity thresholds,.
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HER2 interactions with other biomarkers might enable innovative dual or sequential combination therapies and improve patient selection for emerging front-line and/or salvage treatments in advanced urothelial carcinoma.
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D.R., E.C., F.P. and M.D.G. researched data for the article. D.R., E.C., F.P. and M.D.G. contributed substantially to discussion of the content. D.R., E.C., F.P., P.H.O.’D., B.M.F., P.C.B., P.G., R.A.H. and M.D.G. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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P.G. (in the past 2 years) — consulting with AbbVie, AstraZeneca, Astellas Pharma, Bicycle Therapeutics, Bristol-Myers Squibb, Daiichi Sankyo, Fresenius Kabi, Gilead, Janssen, Merck KGaA, MSD, Pfizer, Roche, Strata Oncology, Replimune, Foundation Medicine, Eli Lilly, Urogen; research funding to the institution: Acrivon Therapeutics, ALX Oncology, Bristol-Myers Squibb, Merck KGaA, MSD, Genentech, Gilead. O.A. received scientific advisory board fees from Seagen, Adaptimmune, Bicycle Therapeutics and Silverback Therapeutics, and research funding to the institution from AstraZeneca, Ikena Oncology, Genentech, and Arcus Biosciences. P.H.O.’D. — honoraria: Adept Field Solutions, Advarra, Merck, Astellas, AbbVie, Pfizer, Custom Learning Designs, Axiom Healthcare Strategies, EMD Serono, IntrinsiQ, ISMIE, ImmunityBio, NAMCP, Seagen, Curio Science, FirstWord, Gilead, MedLearning Group, Research to Practice, Great Debates and Updates, Loxo/Lilly, MJH Life Sciences, Peerview, Vaniam Group, Institute for Enquiring Minds, Pharmavision UK, PRIME Education LLC, Amerisource Bergen, Health Advances, Parexel Intl Corp, Vida Ventures LLC; research funding: Boehringer Ingelheim (Inst), Merck (Inst), Genentech/Roche (Inst), AstraZeneca/MedImmune (Inst), Acerta Pharma (Inst), Janssen (Inst), Seagen (Inst), Bristol-Myers Squibb (Inst), Astellas Pharma (Inst), Pfizer (Inst), Loxo/Lilly (Inst); expert testimony: Hart Wagner LLP, O’Brien and Ryan LLP; travel, accommodation, expenses: Curio Science, Astellas, SeaGen, Merck; other relationships: NIH (via Duke University), Janssen, Nektar, Dragonfly Therapeutics, G1 Therapeutics. R.A.H. — honoraria for advisory boards and speaking from MSD, Roche, Bristol-Myers Squibb, Necktar, Janssen, Merck, Astellas, BioNtech; research funding from MSD, Elekta, Roche, Cancer Research UK. A.N. — employment: Bayer (I); stock and other ownership interests: Bayer (I); consulting or advisory role: Merck Sharp & Dohme, AstraZeneca, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Catalym, Gilead Sciences, Genenta Science, Johnson & Johnson/Janssen, PeerView, PeerVoice, Merck Serono, Samsung Bioepis, Bicycle Therapeutics; research funding: Merck Sharp & Dohme (Inst), Gilead Sciences (Inst), Bristol-Myers Squibb/Celgene (Inst); travel, accommodation, expenses: Merck Sharp & Dohme, AstraZeneca, Janssen, Gilead Sciences. D.R. and R.A.H. acknowledge that this study represents independent research supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
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Raggi, D., Crupi, E., Pederzoli, F. et al. HER2 and urothelial carcinoma: current understanding and future directions. Nat Rev Urol (2025). https://doi.org/10.1038/s41585-025-01075-x
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DOI: https://doi.org/10.1038/s41585-025-01075-x
