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).
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.
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).
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.
BJU international. 2025 Jan 13 [Epub ahead of print]
Csilla Olah, Lara Sichward, Boris Hadaschik, Christopher Darr, Viktor Grünwald, Ulrich Krafft, Barbara T Grünwald, Osama Mahmoud, Mulham Al-Nader, Peter Nyirady, Henning Reis, Tibor Szarvas
Department of Urology, University of Duisburg-Essen, Essen, Germany., Institute of Pathology, University Medicine Essen, University of Duisburg-Essen, Essen, Germany., Department of Urology, Semmelweis University, Budapest, Hungary., Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.