Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes

Abstract

The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer. Staining was scored for intensity (0 to 3) and extent (% positive cells) using the histological score system, where > 15 was considered positive. Overall, 72/83 (87%) samples of nonmuscle invasive urothelial carcinoma were positive, including 29/30 (97%) noninvasive papillary urothelial carcinomas, 7/8 (87.5%) carcinomas in situ, 36/45 (80%) papillary urothelial carcinomas invading the lamina propria. Overall, 50/86 muscle invasive tumors were positive, including 15/22 (68.2%) urothelial carcinomas, 7/10 (70%) squamous cell carcinomas, 3/11 (28%) micropapillary tumors, 4/6 (66%) adenocarcinomas, 2/4 (50%) nested carcinomas, 5/8 (63%) plasmacytoid, 1/10 (10%) sarcomatoid carcinomas, and 0/15 (0%) small cell carcinomas. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugatessacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.

Update in TIGIT Immune-Checkpoint Role in Cancer

“…TIGIT binds NECTIN-4 with high affinity, comparable to CD155 ( 86 ). NECTIN-4 is involved in cell adhesion through trans-homophilic and -heterophilic interactions, including specific interactions with NECTIN-1 (CD111) ( 87 ), does not interact with CD226, CD96, or CD112 ( 86 ), and is overexpressed in several tumors of the breast ( 88 , 89 ), bladder ( 90 ), lung ( 91 , 92 ), and pancreas ( 93 , 94 ).…”

Biomarkers for therapy selection in metastatic urothelial cancer

“…In a recent abstract, NECTIN4 gene expression was found to vary by molecular subtype and was enriched in luminal-type UC. In both luminal and basal bladder cancer cell lines, overexpressing and knocking out NECTIN4 conferred sensitivity and resistance, respectively, to EV in vitro [168] . Nectin-4 protein levels vary by disease stage (87% NMIBC vs. 58% MIBC) and by morphology (e.g., 28% in micropapillary tumors, 63% in plasmacytoid) [169] .…”

Head-to-Head Comparison of the Expression Differences of NECTIN-4, TROP-2, and HER2 in Urothelial Carcinoma and Its Histologic Variants

“…Although it is still unknown whether a high expression of the ADC-corresponding targets is linked to a better efficacy, the expression of these proteins is believed to be essential for the response to ADC as it is the port of entry to tumor cells. The expression of NECTIN-4 in the muscle-invasive UC is reported to be 68.2% ( 20 ), compared with 8.7% of HER2 ( 14 ), and TROP-2 is known to be expressed in normal urothelium and in ≤83% of urothelial carcinoma ( 21 ). However, it is unknown whether the protein expression is related to the clinicopathologic features of the patient.…”