Abstract:
Introduction & objectives: Nectin-4, a membrane protein involved in cell adhesion, has been recently introduced as a target of the novel antibody drug conjugate Enfortumab-Vedotin (EV). However, uniform Nectin-4 overexpression in BC was reported and no predictive capacity from Nectin-4 staining was reported. In the present trial we aimed to determine expression in two independent BC cohorts and further evaluate an alternative IHC interpretation approach for Nectin-4 in advanced BC.
Materials & methods: The study included two independent cohorts consisting of n=97 and 103 patients (70x male, median age 65.5 years, 31x T≤2 – 43x T3 – 23x T4, 76x G>2, 11x M1 and 79x male, 69 years, 31x T≤2 – 48x T3 – 24x T4, 78x G>2, 9x M1, median follow-up 44.5 months, respectively) who underwent radical cystectomy for invasive BC. Tissues from histologically proven BC and from benign urothelium (n=22 and 39) were processed to a tissue microarray and immunohistochemically stained by reported methods (polyclonal rabbit antibody, dilution 1:2000, incubation 16h at 4°, quantified by the histochemical scoring system / H-score 0-300). Results were transferred into four classes: Each cohort was divided into four 25%-classes of successive increasing staining and distribution was demonstrated for each the two BC cohorts. Results were compared to clinical and pathological features.
Results: Mean expression scores in BC and parallel benign urothelium tissue were 133 and 81 / 157 and 114 (p<0.005 / 0.002) with benign urothelium expression correlated with that of corresponding BC (<0.02). The expressions within each patient cohort are lined up as follows: Expression in 25% of the cohort scored low (0-99), of 25% 100-119, of 25% 120-189 and of 25% strong (190-300) in the first cohort, the
second distributed low (0-99) of 25%, 25% 100-165, 25% 166-209 and 25 % strong 210-300. Furthermore, we saw trends of lower expression along progression of MIBC
Conclusion: The assumption that nectin-4 is ubiquitously overexpressed in all urothelial carcinomas, as described in the literature, cannot be confirmed in our results. It could therefore be postulated that the current use of EV without prior determination of the nectin-4 receptor status should be critically reviewed. Furthermore, the question arises to what extent nectin-4 expression could be a predictive biomarker in metastatic bladder cancer.
Nectin-4