Expression of NECTIN-4 and TROP-2 in Resected Upper Tract Urothelial Carcinoma with and Without Preoperative Chemotherapy

Background Antibody-drug conjugates (ADCs) have transformed the treatment of urothelial carcinoma, yet upper tract urothelial cancer (UTUC) data remain limited. Objective We compared NECTIN-4 and trophoblast cell-surface antigen 2 (TROP-2) expression in UTUC specimens from treatment-naive (TN) and chemotherapy (CTX)-exposed patients. Design, setting, and participants A retrospective cohort of 141 consecutive patients with UTUC who underwent resection from 1991 to 2021 was stratified into TN and CTX-exposed cohorts. Outcome measurements and statistical analysis Tissue microarrays were stained for NECTIN-4 and TROP-2 and quantified using the H-score method, with H-score ≥15 and ≥10 defining positivity, respectively. Group comparisons were performed using Wilcoxon rank-sum and Fisher exact tests. Results and limitations NECTIN-4 membrane positivity was observed in 47% (25/53) and 9.3% (8/86) of TN and CTX-exposed specimens, respectively ( p < 0.001), with median H-scores of 8 (interquartile range [IQR] = 0–45) and 0 (IQR = 0–0), respectively ( p < 0.001). TROP-2 membrane positivity was near universal in 100% (52/52) and 97% (83/86) of TN and CTX-exposed specimens, respectively ( p = 0.3), with median H-scores of 280 (IQR = 229–300) and 141 (IQR = 100–197), respectively ( p < 0.001). In patients with distant or local nonurothelial recurrence, membranous TROP-2 and NECTIN-4 were seen in 91% (21/23) and 17% (4/23), respectively. Limitations include a retrospective single-institution design and lack of paired specimens. Conclusions TROP-2 expression was near universal regardless of CTX exposure, including patients who developed recurrence, whereas NECTIN-4 expression was significantly lower in CTX-exposed cohorts. These findings support TROP-2 as a more durable ADC target in UTUC, warranting further investigation of TROP-2–directed ADCs, particularly with prior CTX exposure.