Emergence of human epidermal growth factor receptor 2 as a key biomarker and therapeutic target in advanced urothelial carcinoma

Urothelial carcinoma (UC) represents a significant global health challenge, particularly in its advanced stages where treatment options remain limited and outcomes poor. While platinum-based chemotherapy has historically formed the backbone of first-line treatment for metastatic disease, the median overall survival rarely exceeds 15 months, highlighting the urgent need for more effective therapeutic strategies. The recent molecular characterization of UC has revealed human epidermal growth factor receptor 2 (HER2) as a frequently altered pathway, especially in upper tract UC, where it demonstrates a strong association with high-grade disease and aggressive behavior. The emergence of antibody-drug conjugates targeting HER2 has revolutionized the treatment landscape, offering new hope for patients with HER2-expressing tumors. This comprehensive review contextualizes the recent findings of Huang and He, who published a study in World Journal of Clinical Oncology on HER2 overexpression in upper tract UC within the evolving therapeutic paradigm, emphasizing the critical importance of integrating biomarker-driven strategies, particularly anti-HER2 antibody-drug conjugates in combination with immunotherapy, into the management algorithm of advanced UC. We synthesize evidence from multiple recent studies and clinical trials to provide a thorough overview of the current status and future directions of HER2-targeted therapy in UC.