Expression of Nectin-4 in Variant Histologies of Bladder Cancer and Its Prognostic Value—Need for Biomarker Testing in High-Risk Patients?

Abstract

Variant histologies of bladder cancer (BC) often present with advanced tumor stage and the status of perioperative therapy is unclear. Thereby, squamous cell carcinoma (SCC), adenocarcinoma (ADENO), and sarcomatoid urothelial carcinoma (SARCO) are the most frequent variants. Nectin-4 has emerged as a highly interesting target in BC and might guide therapeutic application of antibody–drug conjugates (ADC). We therefore aimed to investigate expression patterns and prognostic value of Nectin-4 in variant histologies of BC. A single-center retrospective analysis was conducted of patients who underwent radical cystectomy (RC) for BC and revealed variant histologies of BC in the final specimens. Immunohistochemical staining for Nectin-4 was performed on tissue microarrays with 59 SCC, 22 ADENO, and 24 SARCO, and Nectin-4 expression was scored using the histochemical scoring system (H-score). Overall survival (OS) and progression-free survival (PFS) was calculated by Kaplan–Meier method. Median expression of Nectin-4 was 150 (range 0–250) in SCC, 140.5 (range 30–275) in ADENO, and 10 (0–185) in SARCO, with significantly lower levels for SARCO compared to SCC or ADENO (p < 0.001). For SCC, ADENO or SARCO no differences regarding OS or PFS were observed based on Nectin-4 expression levels (p > 0.05). Multivariate analysis revealed nodal stage as an independent prognostic factor for OS and PFS and metastases for PFS but not Nectin-4 expression. In conclusion, Nectin-4 was not prognostic in histological subtypes of BC in our study cohort. However, the high expression of Nectin-4 in SCC and ADENO might guide future treatment with novel Nectin-4-directed ADCs and provide this high-risk patient collective with a new promising therapeutic option. Testing Nectin-4 expression as a biomarker should be considered in trials with SARCO, where low Nectin-4 expression has been observed.

Increased expression of ATP‐binding cassette transporters in enfortumab vedotin‐resistant urothelial cancer

“…Studies have highlighted the heterogeneity in nectin‐4 expression within urothelial cancer, noting a decreased positive rate in muscle‐invasive carcinoma compared with non‐muscle‐invasive carcinoma 10 . Another study reported that variations in nectin‐4 expression rates in different variants of urothelial cancer, with squamous cell carcinoma and adenocarcinoma exhibiting a high positive rate, while sarcomatoid urothelial cancer rarely expresses nectin‐4 11 . Furthermore, it has been reported that nectin‐4 expression is reduced in metastatic lesions compared to primary tumors 12 .…”

“… 10 Another study reported that variations in nectin‐4 expression rates in different variants of urothelial cancer, with squamous cell carcinoma and adenocarcinoma exhibiting a high positive rate, while sarcomatoid urothelial cancer rarely expresses nectin‐4. 11 Furthermore, it has been reported that nectin‐4 expression is reduced in metastatic lesions compared to primary tumors. 12 These findings underscore the importance of assessing nectin‐4 expression, either in the primary or metastatic lesions, before initiating EV therapy.…”

Prognostic Impact of Histologic Subtype and Divergent Differentiation in Patients with Metastatic Urothelial Carcinoma Treated with Enfortumab Vedotin: A Multicenter Retrospective Study

“…In Fan et al's immunohistochemical analysis of 161 surgical specimens stained for nectin-4 [24], membranous positive expression was observed in 79.2%, 100%, 65.2%, 21.1%, 78.9%, and 88.9% of conventional UC, squamous, glandular, neuroendocrine differentiation, micropapillary, and nested subtypes, respectively. Moreover, a single-center retrospective analysis on radical cystectomy for SUC showed that sarcomatoid subtypes had low nectin-4 expression [25]. In 2023, Ghali et al reported the prominent cytoplasmic staining of nectin-4 by a rapid autopsy study [26].…”

P2X1 and P2X7 Receptor Overexpression Is a Negative Predictor of Survival in Muscle-Invasive Bladder Cancer

“…Immunoreactivity of P2XRs was scored using the histochemical scoring system (H-score) as previously described [ 30 ]. The H-score incorporates both the staining intensity and the percentage of stained cells at each intensity level.…”