Prognostic and predictive impact of HER2 expression in metastatic urothelial carcinoma: results from the single-center BladdHER study.

Background: Identifying novel therapeutic targets is a relevant clinical need in mUC. HER2 expression has been gaining increasing relevance after FDA's tumor-agnostic approval of T-Dxd for HER2 positive non-breast malignancies after prior therapies. Prevalence and prognostic relevance of HER2 expression in mUC is still poorly documented. Methods: HER2 expression was retrospectively assessed in pathology samples of pts with mUC starting first line treatment at our Institution from 2016 to 2025. HER2 expression was assessed by IHC. Clinical characteristics and outcomes in terms of response to systemic treatments were then compared between pts with HER2 expressing and negative tumors, respectively. Results: 146 pts were enrolled (78% male, median age 69 years, range 43 to 87 years). HER2 was expressed in 68% of tumors (26% score 1+, 28% 2+, 14% 3+) and negative in 32% of them. FGFR mutations were detected in 18 pts out of 113 tested pts (16%). No correlation was found between HER2 expression and presence of histological variants, presence of FGFR mutations and sites of metastases. Conversely, the HER2 expressing group had a higher rate of bladder primitive site (p<0.001). After a median follow-up of 28.5 months (95% CI 24.7-37.1), HER2 expression was associated with improved DFS (HR 0.67, 95% CI 0.44-1, p= 0.048), OS (HR 0.60, 95% CI 0.37-0.96, p=0.035) and PFS on maintenance Avelumab (HR 0.44, 95% CI 0.20-0.99, p=0.047). HER2 3+ score did not confer prognostic or predictive value. HER2 expression was not associated with differences in first-line PFS (HR 0.77 95% CI 0.50-1.17, p=0.2) or PFS on Enfortumab Vedotin (HR 1.33, 95% CI 0.53-3.33, p=0.5). Conclusions: In our cohort HER2 expression was found in 68% of mUC overall, and appeared to correlate with bladder primitive site, but not with histological variants, sites of metastases and FGFR mutation. Response to chemotherapy appeared comparable among HER2 expressing and HER2 negative pts, whereas the response to avelumab appears to be longer in HER2 expressing pts. The future availability of new HER2 targeting agents will probably have a major impact on the outcomes of HER2 expressing pts.