Expression of Antibody–Drug Conjugate Targets in Urachal and Primary Bladder Adenocarcinomas

Adenocarcinomas of the bladder (<3% of all bladder cancers) comprise two subtypes based on origin: urachal cancer (UrC) and primary bladder adenocarcinoma (PBAC). Treatment strategies for locally advanced or metastatic UrC and PBAC remain poorly defined. Recently, antibody–drug conjugates (ADC) have emerged as a promising therapeutic approach across multiple tumor types, warranting evaluation of their targets in these tumors. In this study, we retrospectively analyzed histologically confirmed rare bladder adenocarcinoma samples, including 25 UrC and 17 PBACs. Protein expression of five ADC therapy-relevant markers (Nectin-4, Trop-2, CEACAM5, Claudin-18, and HER2) was assessed by immunohistochemistry. Potential therapeutic implications were inferred based on target expression, and the prognostic value of these markers was evaluated using Kaplan–Meier survival analysis with the log-rank test. CEACAM5 (CEA) was differentially expressed between UrC and PBAC (p=0.001), while positive Nectin-4 expression was associated with poorer outcomes in UrC patients (p=0.008). Overall, 92% of UrC and 88% of PBAC patients exhibited at least moderate or strong expressions of one or more targetable markers. CEACAM5 was the most frequently expressed target in UrC with positive cases of 96%, whereas Trop-2 was predominated in PBAC with positive cases of 76%. CEACAM5 can be used also as a diagnostic marker for UrC. Moderate or strong Nectin-4, Claudin-18, and HER2 expression was uncommon in both entities. The majority of UrC and PBAC samples highly express at least one potentially targetable protein. However, the expression of specific markers shows high variance, with CEACAM5 and Trop-2 being the most relevant, while Nectin-4, HER2, and Claudin-18 were expressed in only a small subset of patients.