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

Upper tract urothelial carcinoma (UTUC) and urinary bladder cancer (UBC), though histologically similar, differ molecularly, prompting interest in their biomarker profiles for targeted therapies like antibody-drug conjugates (ADCs) enfortumab vedotin (targeting Nectin-4) and sacituzumab govitecan (targeting TROP-2). This study investigated Nectin-4 and TROP-2 expression in 87 UTUC patients, including 54 with a history of concurrent UBC (UTUC + UBC) and 33 with UTUC alone. Immunohistochemical analysis revealed widespread TROP-2 expression (98.8% of samples), with high levels linked to low-grade UTUC (p = 0.043) and intense staining (mean H-score 227 ± 63) across both cohorts. Nectin-4 was expressed in 70.1% of samples overall but was more frequent in the UTUC + UBC group (88.8% vs. 63.6% in UTUC-only patients), though this difference lacked statistical significance (p = 0.340). Notably, Nectin-4 staining intensity was weak in both groups (mean H-score 66 ± 65), suggesting biological distinctions between UTUC with and without UBC. The findings imply that ADCs targeting TROP-2 and Nectin-4 may hold therapeutic promise in UTUC without requiring prior biomarker testing. Additionally, the elevated Nectin-4 expression in UTUC + UBC patients hints at divergent molecular pathways that could influence treatment strategies, warranting further clinical exploration.