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.

Keywords: Nectin-4; adjuvant therapy; antibody–drug conjugate; neoadjuvant therapy; squamous cell carcinoma.

Figure 1

Variant histologies of bladder cancer and Nectin-4 expression levels. (A–D) show representative photomicrographs of tissue microarray (TMA) samples with SCC (A, H&E) and weak (B), intermediate (C), and high Nectin-4 expression (D). (E–H) depict representative photomicrographs of TMA samples with ADENO (E, H&E) and weak (F), intermediate (G), and high Nectin-4 expression (H). (I–K) show representative photomicrographs of TMA samples with SARCO (I, H&E) and weak (J) and intermediate (K) Nectin-4 expression. In SARCO, there was no high Nectin-4 expression detected. H&E, hematoxylin–eosin; SCC, pure squamous cell carcinoma of the bladder; ADENO, adenocarcinoma of the bladder; SARCO, sarcomatoid urothelial carcinoma of the bladder; scale bar 200 µm.

Figure 2

Nectin-4 expression (H-score) in different variant histologies of bladder cancer. Immunohistochemical expression of Nectin-4 for patients with pure squamous cell carcinoma (SCC—black), adenocarcinoma (ADENO—red), and sarcomatoid urothelcarcinoma (SARCO—blue) was evaluated by histochemical scoring system (H-score). Group comparisons were performed by Mann–Whitney U-test; ns: not significant, ****: p < 0.001.

Figure 3

Overall (OS) and progression-free survival (PFS) in variant histologies of bladder cancer. Expression of Nectin-4 was classified as low (H-score < 100, black), intermediate (H-score 100–200, red), and high (H-score > 200, blue). Group comparisons were performed by log-rank test. OS (A) and PFS (B) of squamous cell carcinoma (SCC), OS (C) and PFS (D) of adenocarcinoma (ADENO) and OS (E) and PFS (F) of sarcomatoid urothelicarcinoma (SARCO) were analyzed. In SARCO, there are no patients with a H-score of >200. OS, overall survival; PFS, progression-free survival; SCC, pure squamous cell carcinoma of the bladder; ADENO, adenocarcinoma of the bladder; SARCO, sarcomatoid urothelial carcinoma of the bladder.

Figure 4

Multivariate analysis for OS and PFS in SCC. Age, gender, T-stage (pT), nodal stage (pN), radiological detected metastases (cM), and Nectin-4 expression were used as variables and independent prognostic potential evaluated for OS (A) and PFS (B). p values less than 0.05 were considered as statistically significant and groups are marked in red. * Data are outside of the axis limit due to sample size (HR: 0, 95% CI 1.221 × 10⁻¹⁸⁸ to 1.182 × 10¹⁷⁷).