Prognostic and predictive impact of HER-2 expression in metastatic urothelial carcinoma: Results from the single-centre BLADDHER study.

Abstract

805 Background: Identifying novel therapeutic targets is a relevant clinical need in metastatic urothelial carcinoma (mUC). HER-2 expression has been gaining increasing relevance after FDA's tumor-agnostic approval of Trastuzumab Deruxtecan (T-DxD) for HER2-positive non-breast malignancies after prior therapies. Prevalence and prognostic relevance of HER-2 expression in mUC is still poorly documented. Methods: HER-2 expression was retrospectively assessed in pathology samples of patients (pts) with mUC starting first line treatment at our Institution from 2021 to 2025. HER-2 expression was assessed by immunohistochemistry (IHC) and graded according to gastric tumor score. Clinical characteristics and outcomes in terms of response to systemic treatments were then compared between pts with HER-2 positive and negative tumors, respectively. Results: Eighty-eight pts were enrolled (74% male, median age 73). HER-2 positivity was found in 41% (23% 2+, 18% 3+), 53% were negative (26% 1+, 27% 0), and 6% not evaluable. FGFR mutations were detected in 14 patients (16%). No correlation was found between HER-2 expression and presence of histological variants, presence of FGFR mutations and sites of metastases (Table 1). Conversely, the HER-2 positive group had a higher rate of metastases at diagnosis (p = 0.047) and bladder primitive site (p = 0.005). After a median follow-up of 21.1 months (95% CI 14.9-28.8), HER-2 status was not associated with differences in first-line progression-free survival (PFS) (HR 1.01, 95% CI 0.53-1.91, p > 0.9), overall response rate (ORR) (OR 1.66, 95% CI 0.58-5.02,p = 0.4), or PFS on maintenance Avelumab (HR 1.10,95% CI 0.34-3.49, p = 0.9). Among 23 pts treated with Enfortumab Vedotin in 2nd/3rd line, ORR was not significantly different (OR 6.0, 95% CI 0.74-130, p = 0.14). Conclusions: In our cohort HER-2 positivity was found in 41% of mUC overall, and appeared to correlate with advanced disease at diagnosis and with bladder primitive site, but not with histological variants, sites of metastases and FGFR mutation. Response to cytotoxic and immunological therapies appeared comparable among HER-2 positive and HER-2 negative pts. The future availability of new HER-2 targeting agents will probably have a major impact on the outcomes of HER-2 positive pts. HER-2 positive (N=36) HER-2 negative (N=47) p-value FGFR statuswild typemutated 29 (81%)6 (17%) 35 (76%)8 (17%) 0.8 Histology variantabsentpresent 23 (64%)13 (36%) 29 (62%)18 (38%) 0.8 Metastasic disease at first diagnosis yesno 13 (36%)23 (64%) 8 (17%)39 (83%) 0.047 Primary tumor siteupper tractbladder 4 (11%)31 (89%) 18 (40%)27 (60%) 0.005 Only lymph nodes diseaseyesno 9 (25%)27 (75%) 21 (45%)26 (55%) 0.064 Liver metastasisyesno 5 (14%)31 (86%) 9 (19%)38 (81%) 0.5 Bone metastasisyesno 10 (28%)26 (72%) 6 (13%)41 (87%) 0.086