Abstract HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. While HER2-directed therapies like fam-trastuzumab deruxtecan (T-DXd) are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer (PC) and urothelial carcinoma (UC) remains inadequately characterized. We evaluated HER2 protein expression in metastatic PC and UC using a validated immunohistochemistry 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 PC cohort (n=52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only 5 (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy number gains was observed in some tumors but did not correlate with HER2 protein expression (p=0.2). In UC (n=20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in 6 (30%) cases and 3+ expression observed in 3 (15%) cases in at least one tumor. UC samples showed less heterogeneity, with more consistent expression across metastases. HER2 over-expression is rare and heterogeneous in metastatic PC, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in UC. These findings underscore the importance of comprehensive HER2 assessment in advanced UC and suggests success of HER2-directed therapies in PC will require careful case selection.
Lee et al. (Wed,) studied this question.
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