HER1-HER4 expression and co-expression in advanced urothelial carcinoma.

The human epidermal growth factor receptor (HER) family is under evaluation as a therapeutic target in urothelial cancer (UC); the significance of expression patterns beyond those of HER2 is unclear. Tumour samples from a prospective randomised phase II-III trial (NCT00949455) were analysed by immunohistochemistry (IHC) and RNA profiling. Associations with molecular subtype, chemotherapy response, and overall survival (OS) were explored. The analyses were exploratory, and P values < 0.05 were considered relevant. A total of 446 tumours were tested for HER1/HER2, 77 for HER3, and 79 for HER4 expression. HER1-HER4 were positive (IHC 1-3+) in 89%, 80%, 77%, and 75% of tumours, respectively, with high expression (IHC 3+) in 34%, 12%, 26%, and 29%. Co-expression of all four receptors occurred in 61% of tumours, with concurrent high expression in 9%. Of the tumours, 96% expressed ≥2 receptors. Luminal tumours (n = 109) showed enriched HER2 expression (93% compared with 67%, P < 0.001), and basal tumours (n = 61) showed higher enriched HER3 expression (95% compared with 77%, P = 0.02). HER1 positivity correlated with better chemotherapy responses (P = 0.02) and HER3/HER4 positivity with poorer responses (P = 0.02 and P = 0.03, respectively). No differences in OS were observed. HER1-HER4 are broadly and concurrently expressed in advanced UC, supporting antibody-drug conjugate development beyond HER2. Receptor expression did not correlate with OS.