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

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.