Spatial distribution and subtype-specific expression patterns of Nectin-4 in muscle-invasive bladder cancer

Abstract

Objective: To investigate the expression patterns of Nectin-4, the target molecule of the antibody-drug conjugate enfortumab vedotin (EV), in relation to histological and molecular subtypes of urothelial bladder cancer (UBC).

Patients and methods: We assessed the protein expression patterns of Nectin-4 in a spatially organised tissue microarray containing 1386 tissue cores from 314 consecutive patients with UBC who underwent radical cystectomy (2005-2018). Results were correlated with clinicopathological and follow-up data, as well as with different spatial locations (tumour central vs tumour-normal interface and primary tumour vs lymph node [LN] metastases). Additionally, we correlated Nectin-4 expression levels with histological and molecular subtypes. Finally, we assessed the value of Nectin-4 expression for predicting the efficacy of platinum therapy in the peri-operative setting.

Results: Nectin-4 expression was observed in 63% of primary tumours and 87% of LN metastases, with significantly higher levels in LNs. Of the histological subtypes, the micropapillary (58%) and pure urothelial histologies (30%) were associated with the highest Nectin-4 positivity, while the sarcomatoid (17%), squamous (15%) and small/cell-neuroendocrine (0%) subtypes exhibited the lowest. Nectin-4 immunopositivity rates were significantly higher in luminal (urothelial-like [42%] and genomically unstable [34%] Lund subtypes) compared to the basal (5%) or mesenchymal (0%) molecular subtypes. Higher Nectin-4 expression levels were associated with lower tumour stage but showed no association with overall survival. Finally, patients with low Nectin-4 expression tended to derive more benefit from platinum-based chemotherapy in both adjuvant and neoadjuvant settings (P < 0.001, P = 0.067).

Conclusion: Our results revealed a low spatial heterogeneity of Nectin-4 expression within the primary tumour. In contrast, differential Nectin-4 expression was found in the context of histological and molecular subtypes. Nectin-4-expressing tumours may show varying sensitivity to both EV and platinum-based chemotherapy.

Keywords: bladder cancer; cisplatin; enfortumab vedotin; immune checkpoint inhibitor; immunohistochemistry; molecular subtype; nectin‐4.

Fig. 1

Nectin‐4 expression in different tumour localisations: (A) the tumour central (TC) region, (B) the corresponding positive lymph nodes and(C) at different tumour stages. (D) Forest plot presentation of the associations of various clinicopathological factors and Nectin‐4 expression with patients' overall survival. HR, hazard ratio; IHC, immunohistochemistry; LN+, positive lymph node; M+, presence of distant metastasis; TNI, tumour‐normal interface.

Fig. 2

Nectin‐4 expression in different (A) histological subtypes and (B) molecular subtypes in the tumour central region. (C) Correlation between the expression of Nectin‐4 and 13 molecular subtype markers. Statistical significance: **P ≤ 0.01 and *P ≤ 0.05 in plot C. BA/SQ, basal/squamous; CC, clear‐cell; GL, glandular; GU, genomically unstable; IHC, immunohistochemistry; LELC, lymphoepithelioma‐like; Mes, mesenchymal‐like; MPUC, micropapillary urothelial carcinoma; NOS, urothelial carcinoma without subtype/not otherwise specified; PUC, plasmacytoid; SARC, sarcomatoid; Sc/NE, small‐cell/neuroendocrine; Sq, squamous; Uro, urothelial‐like.