HER2 in Bladder Cancer: Molecular Biology, Prognostic Value, and Emerging Therapeutic Strategies

Introduction: Non-muscle invasive bladder cancer (NMIBC) accounts for nearly 75–80% of newly diagnosed bladder cancers and is marked by frequent recurrence and a variable risk of progression. Human epidermal growth factor receptor 2 (HER2) has emerged as a biologically relevant oncogenic driver in urothelial carcinoma, but its prognostic and therapeutic significance in NMIBC remains incompletely defined. Aim: This review synthesises current evidence on HER2 biology, molecular associations, prognostic relevance, and therapeutic implications in bladder cancer, with a focus on NMIBC. Results: HER2 overexpression and amplification are enriched in high-grade tumours, advanced stages, luminal molecular subtypes, and aggressive histological variants, and are associated with disease progression and resistance to intravesical BCG therapy. Despite strong biological rationale, conventional HER2-targeted therapies have shown limited efficacy in urothelial carcinoma due to heterogeneous expression, discordance between protein overexpression and gene amplification, and complex downstream signalling. In contrast, emerging antibody–drug conjugates demonstrate promising clinical activity, including in tumours with low or heterogeneous HER2 expression. Conclusion: HER2 represents a clinically meaningful biomarker and therapeutic target in bladder cancer. Standardised HER2 assessment integrated with molecular profiling may refine risk stratification and enable precision-guided therapies, particularly for patients with high-risk or treatment-refractory NMIBC.