This study systematically analyzes the expression profiles of Nectin-4 and TROP-2 in upper tract urothelial carcinoma (UTUC) and explores their associations with disease grading and therapeutic strategies. Results demonstrate widespread TROP-2 expression (98.8%) correlated with low-grade tumors, while Nectin-4 shows lower expression levels, suggesting potential utility as targets for antibody-drug conjugate (ADC) therapies.
Literature Overview
The article '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 evaluates Nectin-4 and TROP-2 expression in 87 UTUC patients using immunohistochemistry (IHC) with H-score quantification. Among them, 54 patients had prior urinary bladder cancer (UBC) history. Findings reveal TROP-2 exhibits high expression (98.8%) in UTUC, with stronger intensity in low-grade tumors, whereas Nectin-4 shows 70.1% expression. Notably, Nectin-4 expression appears higher in patients with UBC history (88.8% vs. 63.6%), though without statistical significance. The study highlights their potential as ADC targets and suggests expression patterns may reflect molecular heterogeneity between UTUC and UBC.
Background Knowledge
Upper tract urothelial carcinoma (UTUC) is a rare but aggressive subtype accounting for 5–10% of all urothelial cancers. Compared to urinary bladder cancer (UBC), UTUC demonstrates distinct molecular features and therapeutic responses, indicating divergent tumor microenvironments and biological behaviors. With expanding applications of antibody-drug conjugates (ADCs) in urothelial malignancies, TROP-2-targeted sacituzumab govitecan and Nectin-4-targeted enfortumab vedotin have shown clinical benefits in advanced stages. However, the expression landscape of these targets in UTUC, particularly among patients with UBC history, remains unclear and may influence ADC treatment decisions. This study aims to address these gaps by systematically evaluating TROP-2 and Nectin-4 expression patterns in UTUC and their correlations with tumor grade and prior UBC history.
Research Methods and Experiments
This study included 87 non-metastatic UTUC patients treated with radical nephroureterectomy or laser ablation at Hannover Medical School between 2010 and 2023. Of these, 54 cases (62.1%) had prior UBC history while 33 had isolated UTUC. Immunohistochemical (IHC) analyses were performed using VENTANA BenchMark ULTRA automated staining system. TROP-2 and Nectin-4 expression levels were quantified through H-score (intensity × percentage of stained cells). Statistical comparisons between diagnostic groups utilized Mann–Whitney U tests or chi-square tests.
Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the first systematic comparison of TROP-2 and Nectin-4 expression profiles in UTUC, supporting their potential as ADC targets. While no statistically significant differences were observed, expression trends suggest patients with prior UBC history may derive greater benefit from Nectin-4-directed therapies. Future studies with larger cohorts are needed to validate these expression patterns and establish clinical correlations. Standardization of H-score thresholds and determination of clinically relevant expression levels remain critical for optimizing ADC patient selection and predicting therapeutic responses.
Conclusion
This study confirms widespread expression of TROP-2 and Nectin-4 in UTUC, particularly noting TROP-2's high prevalence (98.8%) which supports its potential as an ADC target. Enhanced TROP-2 expression in low-grade tumors suggests its value as a prognostic biomarker. Although Nectin-4 shows elevated expression in patients with UBC history, this difference lacks statistical significance. The findings emphasize that biomarker testing may not be mandatory before targeted therapies, but recommend integrating clinical treatment data in future studies to validate predictive values. These results provide preliminary evidence for personalized ADC therapy in UTUC while establishing directions for subsequent investigations.
