Title : Temporal changes in HER2 and nectin4 expression in urothelial carcinoma: Implications for antibody–drug conjugate therapy
Abstract:
Background: Urothelial carcinoma is frequently managed with chemotherapy combined with immunotherapy or antibody-drug conjugates (ADCs) targeting HER2 and Nectin4, which have shown promising efficacy in clinical practice. However, treatment response often diminishes over time, potentially due to alterations in target expression. Previous studies indicate that target heterogeneity exists across tumor sites, but dynamic changes in expression at the same site over time remain underexplored.
Methods: We conducted a retrospective analysis of 129 urothelial carcinoma patients treated at our center over 5 years, all with at least two pathological evaluations. Changes in HER2 and Nectin4 expression levels were assessed between initial and follow-up biopsies.
Results: HER2 expression was downregulated in 78 cases (e.g., from 3+ to 2+ or 1+), and Nectin4 expression was downregulated in 64 cases. This suggests a high incidence of target loss during treatment.
Conclusion: The observed downregulation of HER2 and Nectin4 may contribute to the reduced efficacy of ADC therapies over time. Monitoring these expression changes could inform optimal treatment duration and sequencing strategies, potentially enhancing personalized therapy approaches.
Keywords: Urothelial Carcinoma, HER2, Nectin4, Antibody-Drug Conjugates, Expression Downregulation, Treatment Resistance.
