Patterns of HER2 Expression in Metastatic Prostate and Urothelial Cancers: Implications for HER2-Targeted Therapies.

HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. Although HER2-directed therapies like fam-trastuzumab deruxtecan are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer and urothelial carcinoma remains inadequately characterized. We evaluated HER2 protein expression in metastatic prostate cancer and urothelial carcinoma using a validated IHC assay on tissue microarrays constructed from the University of Washington Tissue Acquisition Necropsy Program. HER2 expression was scored using standardized gastric cancer criteria. Genomic analysis of ERBB2 alterations was conducted on a subset of samples. HER2 expression heterogeneity and its relationship with other surface markers were also evaluated. In the prostate cancer cohort (n = 52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only five (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy-number gains were observed in some tumors but did not correlate with HER2 protein expression (P = 0.2). In urothelial carcinoma (n = 20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in six (30%) cases and 3+ expression observed in three (15%) cases in at least one tumor. Urothelial carcinoma samples showed less heterogeneity, with more consistent expression across metastases. HER2 overexpression is rare and heterogeneous in metastatic prostate cancer, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in urothelial carcinoma. These findings underscore the importance of comprehensive HER2 assessment in advanced urothelial carcinoma and suggest that success of HER2-directed therapies in prostate cancer will require careful case selection.

Significance: This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer and suggest that HER2-targeted therapies in prostate cancer will require careful patient selection.