Huang L, He J. Human epidermal growth factor receptor 2 overexpression is associated with high-grade tumors in upper tract urothelial carcinoma. World J Clin Oncol 2025; 16(10): 110047 [PMID: 41178915 DOI: 10.5306/wjco.v16.i10.110047]
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00735730
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October 29, 2025, 19:59
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Reader Comments:
The retrospective study by Huang and colleagues provides valuable insights into the prevalence and clinicopathological significance of HER2 expression in upper tract urothelial carcinoma. Their finding that HER2 overexpression is strongly associated with high tumor grade but not with conventional markers of disease progression underscores the distinct biological behavior of UTUC compared to bladder cancer. This work is particularly relevant as it highlights a potential therapeutic target in a disease with limited treatment options. However, the clinical implications of HER2 expression in UTUC must now be reinterpreted in light of the practice changing results presented at the ESMO Congress 2025. The phase 3 RC48 C016 trial demonstrated for the first time that a combination of the anti HER2 antibody drug conjugate disitamab vedotin and the anti PD1 immunotherapy toripalimab significantly outperforms standard platinum based chemotherapy in the first line treatment of HER2 expressing locally advanced or metastatic urothelial carcinoma. The results are striking: Progression free survival was nearly doubled (13.1 months versus 6.5 months; HR = 0.36); Overall survival showed a remarkable improvement (31.5 months versus 16.9 months; HR = 0.54); Benefits were consistent across all HER2 expression levels (IHC 1+, 2+, and 3+); and The combination also exhibited a more favorable safety profile. These findings represent a paradigm shift. For the first time, a biomarker directed strategy has proven superior to chemotherapy in the first line setting for advanced UC. Given that HER2 expression is found in up to 70% of urothelial carcinomas, this new regimen could benefit a majority of patients. In this context, the work by Huang et al gains even greater importance. Their observation that nearly half of UTUC tumors (46.2%) show HER2 positivity especially in high grade disease suggests that a substantial proportion of UTUC patients may be candidates for this novel, highly effective combination therapy. The authors call for clinical trials evaluating HER2 targeted therapies in high grade, HER2 positive UTUC is now more urgent than ever. Future studies should urgently validate the efficacy of disitamab vedotin plus toripalimab in UTUC specific cohorts and explore its potential in earlier disease stages. The era of biomarker driven therapy for urothelial carcinoma has arrived, and HER2 is firmly at its center.
Reference: Sheng X, He Z, Zhang G, et al. Primary results from the phase 3 RC48 C016 trial: Disitamab vedotin plus toripalimab versus chemotherapy as first line treatment for HER2 expressing locally advanced or metastatic urothelial carcinoma. Annals of Oncology 2025;36(Supplement 3):S1573 S1574.