NECTIN4 Expression in Advanced Urothelial Carcinoma and Implications for Treatment

A recent study demonstrates significant correlations between NECTIN4 mRNA expression and clinical outcomes in patients with advanced urothelial carcinoma (UC). The findings suggest that NECTIN4 expression could serve as a potential biomarker for selecting patients who are likely to benefit from enfortumab vedotin (EV) therapy, marking a notable advancement in the treatment of this aggressive cancer.

Recent treatments for advanced UC, particularly antibody-drug conjugates (ADCs) like EV, have significantly improved patient outcomes. However, no biomarkers are currently available to predict response to these therapies. Researchers hypothesized that the therapeutic benefit of EV might be associated with the expression levels of NECTIN4, the gene encoding the cell surface antigen targeted by EV.

The study, conducted by Tyler F. Stewart, MD, of the University of California, San Diego, Moores Cancer Center in La Jolla, California, and colleagues analyzed bladder and upper tract UC samples using NextGen DNA sequencing and whole transcriptome RNA sequencing. The samples were stratified into quartiles based on NECTIN4 mRNA levels. Tumor mutational burden (TMB) and other genetic markers were also assessed. Survival outcomes were calculated using Kaplan-Meier estimates, with overall survival (OS) measured from sample collection and treatment initiation to the last follow-up.

A total of 6395 patient samples were analyzed, with 4335 coming from primary tumors (3496 bladder/urethra, 839 upper tract) and 2060 from metastases. The study found that higher NECTIN4 expression was associated with several genetic alterations, including increased mutation rates in FGFR3, ERBB2, pTERT, CCNE1, and SDHC. Additionally, higher NECTIN4 levels correlated with TMB-high status but showed lower rates of TP53 mutations.

NECTIN4 expression also positively correlated with the expression of TACSTD2 (TROP2), ERBB2 (HER2), and SLITRK6, while inversely correlating with PD-L1 expression. These correlations were consistent across primary bladder and upper tract tumors and across primary versus metastatic sites.

NECTIN4 expression was additionally linked to improved oncologic outcomes. Patients with higher NECTIN4 levels had longer OS and time on treatment with EV. Specifically, the top quartile of NECTIN4 expression showed a median OS of 21.1 months compared with 13.8 months in the bottom quartile (hazard ratio [HR], 0.76). Among patients treated with EV, the top quartile had a median OS of 18.0 months versus 12.9 months in the bottom quartile (HR, 0.67).

This comprehensive analysis highlights the potential of NECTIN4 RNA expression as a biomarker for predicting response to EV in advanced UC. “The results of this study suggest that NECTIN4 expression could guide the selection of patients for EV therapy, offering a more personalized approach to treatment,” the study authors wrote.