Expression of Nectin‐4 and Trop‐2 in upper tract urothelial carcinoma: implications for biomarker‐driven antibody‐drug conjugate therapy

Abstract Recent advancements in antibody‐drug conjugates, including FDA‐approved therapies targeting Nectin‐4 and Trop‐2, have transformed the cancer treatment landscape, including upper tract urothelial carcinoma (UTUC). However, varied treatment effects and drug‐associated adverse effects raise the question of whether patients should be selected based on a biomarker study to achieve optimal outcomes. A better understanding of the patterns and clinicopathological significance of Nectin‐4 and Trop‐2 expression in UTUC remains to be achieved. We generated tissue microarrays (TMAs) with 120 UTUC specimens from patients who underwent nephroureterectomy at our institution and evaluated the expression of Nectin‐4 and Trop‐2 in tumor and non‐tumor tissue. Nectin‐4 expression was significantly higher in both invasive and noninvasive high‐grade UTUC compared to noninvasive low‐grade tumors. In contrast, Trop‐2 expression did not vary significantly between noninvasive low‐grade and high‐grade tumors. When analyzed by stage, Nectin‐4 expression was significantly elevated in tumors of higher stages than in early‐stage tumors, similar to Trop‐2 expression. Although both Nectin‐4 and Trop‐2 were broadly expressed in tumor and adjacent non‐tumor urothelium, a subset of patients demonstrated low expression in non‐tumor tissue but high expression in tumor tissue. Nectin‐4 expression, but not Trop‐2, was significantly correlated with the Ki‐67 index, indicating that they may have different roles in tumor proliferation. The differential expression of Nectin‐4 and Trop‐2 by tumor grade and stage highlights their potential relevance in guiding targeted therapy for UTUC. Notably, a subset of patients exhibits high expression in tumor tissue, accompanied by low expression in adjacent non‐tumor urothelium, suggesting a favorable therapeutic index for antibody‐drug conjugate therapy. These findings support the need for further biomarker‐driven studies to optimize patient selection and treatment outcomes.