Membranous NECTIN-4 Expression Often Decreases During UC Metastases

By Zachary Bessette - January 3, 2023

A study published in Clinical Cancer Research found that membranous NECTIN-4 expression is frequently decreased or absent altogether in metastatic urothelial carcinoma (UC) tissue.

This finding correlates with enfortumab vedotin (EV) resistance, researchers added.

EV is the first approved antibody-drug conjugate for patients with metastatic UC without prior assessment of tumor receptor status because NECTIN-4 expression is assumed.

A group of German researchers sought to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors and patient-matched distant metastases. NECTIN-4 protein expression was measured by immunohistochemistry in primary tumors and corresponding metastases (n=137) as well as in a multicenter EV-treated cohort (n=47).

Progression-free survival (PFS) after initiation of EV treatment was evaluated for the NECTIN-4 expression negative or weak (score, 0-99) versus moderate or strong (score, 100-300) subgroups.

Results of the analysis showed membranous NECTIN-4 protein expression significantly decreased during metastatic spread (Wilcoxon matched pairs P<.001; median score=40; interquartile range, 0-140). Approximately 39% of metastases did not show membranous NECTIN-4 expression.

Furthermore, researchers found that absence of or weak membranous NECTIN-4 expression (34.0% of the multicenter EV cohort) was associated with a significantly shortened PFS on EV treatment (log-rank P<.001).

“Our results are of highest clinical relevance and argue for a critical reconsideration of the current practice,” study authors concluded, adding that “the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.”