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. 2025 Aug 1;5(8):1419-1428.
doi: 10.1158/2767-9764.CRC-25-0069.

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

Hyun Jung Lee  1   2   3 , Roman Gulati  4 , Erolcan Sayar  5 , Radhika A Patel  5 , Pushpa Itagi  5 , Helen M Richards  5 , Thomas Persse  5 , Sonali Arora  5 , Ilsa Coleman  5 , Mohamed Adil  5 , Samantha L Schuster  5 , Farinaz Shokri  5 , Jonathan L Wright  6 , Evan Y Yu  4   7 , Lawrence D True  1 , Meagan Chambers  8 , Jessica E Hawley  4   7 , Heather H Cheng  4   7 , Michael T Schweizer  4   7 , Petros Grivas  4   7 , Peter S Nelson  5   7 , R Bruce Montgomery  4   7 , Andrew C Hsieh  5   7 , Funda Vakar-Lopez  1   5 , Colm Morrissey  6 , Hung-Ming Lam  6 , Gavin Ha  5 , Maria S Tretiakova  1 , Michael C Haffner  1   4   5 , Ruben Raychaudhuri  4   7
Affiliations

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

Hyun Jung Lee et al. Cancer Res Commun. .

Abstract

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.

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Conflict of interest statement

R. Gulati reports grants from NCI during the conduct of the study. J.L. Wright reports grants from Merck, Nucleix, Seagen, and Janssen, grants and other support from Pacific Edge, and other support from Immunity Bio and UpToDate outside the submitted work. E.Y. Yu reports personal fees from Johnson & Johnson, AstraZeneca, Tolmar, Bristol Myers Squibb, Loxo, Novartis, and Aadi Bioscience, grants and personal fees from Lantheus, Merck, and Bayer, and grants from Dendreon, Pfizer, Blue Earth, and Tyra outside the submitted work. J.E. Hawley reports other from Johnson & Johnson outside the submitted work. H.H. Cheng reports grants from Clovis Oncology, Janssen, Promontory Therapeutics, Medivation, and Sanofi outside the submitted work. M.T. Schweizer reports personal fees from Sanofi, Fibrogen, and Daiichi Sankyo, grants from Novartis, Zenith Epigenetics, Eli Lilly and Company, Bristol Myers Squibb, Merck, Immunomedics, Tmunity, SingalOne Bio, Epigenetix, Xencor, Incyte, Ambrx, AstraZeneca, and Oric Pharmaceuticals, and grants and personal fees from Janssen and Pfizer outside the submitted work. P. Grivas reports grants and personal fees from Bristol Myers Squibb, MSD, EMD Serono, and G1 Therapeutics, grants, personal fees, and nonfinancial support from Gilead Sciences, grants from Acrivon Therapeutics, ALX Oncology, Genentech, Mirati Therapeutics, and QED Therapeutics, and personal fees from AstraZeneca, Pfizer, Janssen, Roche, Astellas Pharma, Fresenius Kabi, PureTech, Aadi Bioscience, CG Oncology, Strata Oncology, ImmunityBio, Asieris Pharmaceuticals, AbbVie, Bicycle Therapeutics, Replimune, Daiichi Sankyo, Foundation Medicine, Urogen, Eli Lilly and Company, and Tyra Biosciences outside the submitted work. P.S. Nelson reports personal fees from Janssen, Genentech, AstraZeneca, and Pfizer and grants from Janssen outside the submitted work. M.C. Haffner reports other support from Novartis, Genentech, Bristol Myers Squibb, and Promicell and personal fees from Pfizer and AstraZeneca outside the submitted work. R. Raychaudhuri reports grants from NIH/NCI during the conduct of the study. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
A and B, Representative micrographs of HER2 IHC staining in prostate cancer (A) and urothelial cancer (B) autopsy specimens. C, Number of patients with at least one tumor with the indicated HER2 IHC score, color coded by cancer type. D, Number of tumors across all patients with the indicated HER2 IHC score, color coded by cancer type. E and F, Percent of tumors expressing the indicated level of HER2 staining by IHC according to the tumor site sampled in prostate (E) and urothelial (F) cancer cohorts. Anatomic sites with only one representative tumor were excluded. PC, prostate cancer; UC, urothelial carcinoma.
Figure 2
Figure 2
A and B, Mosaic plots indicating the relationship between ERBB2 genomic status as assessed by unadjusted copy number and HER2 IHC in (A) prostate and (B) urothelial cancers. C and D, Box plots indicating the relationship between HER2 RNA expression with (C) prostate and (D) urothelial cancers. PC, prostate cancer; UC, urothelial carcinoma.
Figure 3
Figure 3
A and B, Box plots indicating the relationship between HER2 score with protein expression of key cell surface antigens as measured by IHC in (A) prostate cancer and (B) urothelial cancer.
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