Nectin-4 and Trop-2 expression in collecting duct carcinoma: new promising therapeutic targets

BACKGROUND: Collecting duct carcinoma (CDC) is a rare and aggressive renal malignancy with limited therapeutic options and no established biomarker-driven strategies. Given its morphologic and embryologic overlap with urothelial carcinoma, we investigated the expression of Nectin-4 and Trop-2, targets of antibody-drug conjugates (ADCs) with proven activity in urothelial cancer. PATIENTS AND METHODS: Tumor samples from 59 patients with CDC who were enrolled in the multicenter CICERONE study (NCT05372302) were centrally reviewed by expert genitourinary pathologists. Immunohistochemical analyses for Nectin-4 and Trop-2 were carried out on formalin-fixed, paraffin-embedded tissue. Tumors were considered positive when >10% of cells showed membranous and/or cytoplasmic staining. RESULTS: Nectin-4 expression was detected in 41% of cases, with variable staining intensity, while Trop-2 expression was observed in 89% of tumors, frequently showing strong and diffuse staining. No substantial associations were found between marker expression and clinicopathologic features. CONCLUSIONS: Nectin-4 and Trop-2 are frequently expressed in CDC, supporting a biological overlap with urothelial carcinoma. Although these findings do not imply clinical efficacy, they provide a rationale for prospective evaluation of ADC-based strategies in this rare malignancy, including ongoing clinical trials investigating enfortumab vedotin-based combinations.