Concordance and prognostic value of antibody drug conjugate and checkpoint inhibition targets in matched bladder cancer specimens from transurethral resection of the bladder, radical cystectomy and lymphadenectomy

BACKGROUND: Concordance of NECTIN-4 gene and protein expression and clinic-pathologic associations in matched bladder cancer (BC) triplets, defined as histological specimens from transurethral resection of the bladder (TUR-B), radical cystectomy (RC), and lymphadenectomy (LA) from the same patient, remains unknown. With Enfortumab Vedotin (EV) potentially moving into earlier treatment settings, understanding expression of NECTIN-4 and other targets in archival tissue samples is important. This study characterized protein expression of NECTIN-4 and gene expression of NECTIN4, TACSTD2, ERBB2, PD-L1 and PD1 in matched BC triplet specimens and correlated findings with survival endpoints. METHODS: This retrospective study analyzed NECTIN-4 protein expression and gene expression of 6 target genes using immunohistochemistry and quantitative real-time polymerase chain reaction in matched TUR-B, RC, and LA tissue samples from 27 patients with BC. NECTIN-4 was validated in 3 independent BC cohorts. Protein and gene expression were correlated with clinic-pathologic characteristics. Prognostic associations with survival were analyzed using Kaplan-Meier estimates, log-rank tests and Cox proportional hazard models. RESULTS: Median NECTIN-4 protein expression differed significantly across tissues types with highest levels in TUR-B, lower levels in RC, and intermediate levels in LA specimens Quantitative analysis confirmed significant differences in H-scores across specimens. Expression of NECTIN-4, TACSTD2, PD-L1 and ERBB2 varied significantly across triplets. NECTIN-4 protein expression was not associated with overall or progression-free survival, whereas NECTIN-4 gene expression showed significant but contradictory survival associations in different BC cohorts. CONCLUSION: NECTIN-4 expression differs by tissue type, limiting prognostic value and supporting site-specific biomarker assessment in BC.