Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review

Aberrant expression of nectin-4 (N4) has been observed in several malignancies emerging as new target for antibody-drug conjugates, especially in urothelial carcinoma of the bladder (UBC). Limited data on N4 positivity in nonurothelial genitourinary (GU) cancers are available. This systematic-review aimed to investigate N4 positivity among GU malignancies.

A systematic literature review was performed on March 2023 using PubMed, MEDLINE, and Embase databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Protocol was amended to incorporate a new updated search on March 2024.

Twenty-five studies evaluating N4 positivity in GU tumors were included, 14 on UBC, three on upper tract urothelial carcinoma (UTUC), six on histologic subtypes (HS) and divergent histology of the bladder, one on papillary renal cell carcinoma (pRCC), one in chromophobe RCC (chRCC), two on penile cancer, one in prostate cancer (PCa). Among UBC, stratifying per stage N4 positivity was higher in metastatic (weighted mean [WM], 90.8; range, 59.6-100) and in non-muscle-invasive (WM, 87.4; range, 86.7-88.3) than in muscle-invasive UC (WM, 83.1; range, 68.2-100). The N4 positivity of UBC was higher than UTUC (WM, 62.9; range, 44.4-65.7). Immunohistochemistry N4 positivity was reported to be lower in non-UC malignancies, including pRCC (WM, 44.1; range, 44.1-44.1), HS (WM, 63.5; range, 0-100), PCa (WM0; range, 0-0), chRCC (WM, 18.5; range, 18.5-18.5), and penile cancer (WM, 86.5; range, 61.4-98.3), compared with UBC overall (WM, 87.1; range, 59.6-100).

Non-UC malignancies seem to have a lower N4 positivity rate than UC. N4 positivity in bladder cancer appears to vary according to stage and presence of HS. The predictive and prognostic role of N4 must be further characterized in larger and prospective studies.