This study systematically analyzed the expression profiles of Nectin-4 and TROP-2 in upper tract urothelial carcinoma (UTUC) and explored their associations with tumor grading and therapeutic strategies. The research demonstrates TROP-2's widespread high expression in UTUC (98.8%) with stronger expression in low-grade tumors, while Nectin-4 shows lower expression (70.1%) but potential clinical relevance for antibody-drug conjugate (ADC) therapies.
Literature Overview
This article titled 'Comparison of molecular profiles (Nectin-4 and TROP-2) in upper tract urothelial carcinoma with a positive history of urinary bladder cancer vs. UTUC only in the era of ADCs' published in BMC Cancer systematically evaluated Nectin-4 and TROP-2 expression in 87 UTUC patients, including 54 with prior urinary bladder cancer (UBC) history, using immunohistochemistry (IHC) and H-score quantification. TROP-2 exhibited significantly higher expression in low-grade UTUC (H-score mean 227 ± 63), suggesting potential prognostic value. While Nectin-4 showed differential expression between cohorts (88.8% vs. 63.6%), the difference lacked statistical significance. The study highlights molecular heterogeneity between UTUC and UBC and underscores the importance of these targets for ADC development.
Background Knowledge
Upper tract urothelial carcinoma (UTUC) represents a rare but more aggressive subtype of urothelial carcinoma, accounting for 5–10% of all cases. Compared with bladder urothelial carcinoma (UBC), UTUC demonstrates distinct molecular characteristics and treatment responses, indicating differences in tumor microenvironment and biological behavior. With increasing ADC applications in urothelial cancers, particularly TROP-2-targeted sacituzumab govitecan and Nectin-4-targeted enfortumab vedotin showing efficacy in advanced stages, understanding the expression patterns of these targets in UTUC becomes critical. This study addresses current knowledge gaps regarding target expression profiles in UTUC patients with and without UBC history, providing molecular evidence for personalized ADC strategies.
Research Methods and Experiments
The study included 87 non-metastatic UTUC patients treated at Hannover Medical School between 2010 and 2023, comprising 54 with prior UBC history (62.1%) and 33 with isolated UTUC. IHC analysis was performed using the VENTANA Benchmark ULTRA automated staining system, with TROP-2 and Nectin-4 expression quantified by H-score (intensity × percentage of stained cells). Statistical comparisons between groups utilized Mann–Whitney U tests or chi-square tests.
Key Conclusions and Perspectives
Research Significance and Prospects
This work establishes the first systematic characterization of TROP-2 and Nectin-4 expression in UTUC, validating their potential as ADC targets. The observed expression trends suggest UBC-history patients might benefit more from Nectin-4-targeted therapies, though requiring further validation. Future studies should employ larger cohorts to confirm expression dynamics, integrate clinical treatment response data for predictive value assessment, and standardize H-score thresholds for optimized patient selection in ADC therapies.
Conclusion
This research confirms the prevalent expression of TROP-2 and Nectin-4 in UTUC, particularly highlighting TROP-2's exceptional expression rate (98.8%) and its inverse correlation with tumor grade. While Nectin-4 shows differential expression patterns between patient groups, the lack of statistical significance suggests caution in interpreting clinical implications. The findings support the potential of both proteins as ADC targets in UTUC, emphasizing the need for integrated biomarker-clinical studies to establish their predictive value and guide precision oncology approaches.
