Assessing HER2 expression in metastatic prostate and urothelial cancers

Distinguishing cancer cells from healthy cells is a central challenge in cancer treatment. Ideal therapies selectively kill cancer cells while leaving healthy cells healthy and able to perform their necessary functions. A common treatment approach involves identifying cancer cells by abnormal protein expression on the cell surface. In breast cancer, the surface protein Human Epidermal growth factor Receptor 2 (HER2), a tightly regulated protein that promotes cell growth and division, is overexpressed in about 20% of cases. Overexpression of HER2, whether caused by a genetic mutation or a regulatory malfunction, can contribute to the uncontrolled cell growth characteristic of cancer.  

HER2-targeted therapies effectively treat up to 90% of HER2-positive breast cancers. This success has led researchers to wonder whether HER2 therapies may be able to treat other solid tumor cancers. The question is, what other cancers overexpress HER2?

In a recent study published in Cancer Research Communications, Drs. Ruben Raychaudhuri and Michael Haffner in the Clinical Research Division and colleagues characterized the HER2 expression landscape in advanced metastatic prostate and urothelial (urinary tract) cancers.  The team collected biopsies of tumors from patients who had recently passed away and measured HER2 protein expression in each tumor on a standard scale, from 0 indicating no expression to 3+ indicating high expression. This scale is already commonly used to clinically classify HER2 expression in other cancers.

Across 358 tumors from 52 metastatic prostate cancer patients, no tumors showed high overexpression (3+) of HER2. Only 5 patients had a tumor with medium overexpression (2+), and in these patients, the likelihood of a second tumor at another site also overexpressing HER2 was just 10%. The overall low HER2 expression levels mean that HER2-directed therapies are unlikely to be successful in treating advanced prostate cancer.

However, the results were different for metastatic urinary tract cancer. The team analyzed 68 tumors in 20 patients. Three of these patients (15%) had at least one tumor with high HER2 overexpression (3+), and the likelihood of another tumor also highly overexpressing HER2 was 88%. This suggests that HER2-targeted therapies may be a viable treatment approach for some metastatic urothelial cancer patients.

The research team was interested in understanding what was causing HER2 overexpression in the urothelial cancer.  They analyzed the gene that encodes HER2, ERBB2, in tumors. They found that in one patient, there was an activating mutation in the ERBB2 coding sequence and in others, the gene had multiplied such that the cancer cells contained multiple copies. Importantly, there were several tumors that overexpressed HER2 but did not have detected genetic modifications, highlighting the necessity of direct cell surface protein measurement rather than genetic analysis to determine tumor HER2 positivity.

Because the success of HER2-targeted therapies depends on HER2 overexpression in cancer cells, it is always necessary to biopsy tumors in cancer patients when deciding whether to implement this approach. However, not all tumors are the same, even within a single patient. Some may overexpress HER2 while others may not. In patients with metastatic disease, it is not possible to biopsy all tumors, so understanding generally how consistent or inconsistent HER2 expression is across tumors in each cancer type is vital for guiding clinical decisions on whether to pursue a HER2-targeted therapy. The results of this study show that HER2 expression is relatively consistent across tumors in various anatomical sites in advanced metastatic urothelial cancer, but not in metastatic prostate cancer. This supports exploring HER2-targeted therapies for treating advanced metastatic urothelial disease.  It also raises the question, what other hard-to-treat cancers consistently overexpress HER2?  How broadly applicable are HER2-targeted therapies? 

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Jonathan Wright, Evan Yu, Lawrence True, Heather Cheng, Michael Schweizer, Petros Grivas, Peter Nelson, Bruce Montgomery, Andrew Hsieh, Funda Vakar Lopez, Colm Morrissey, Hung-Ming Lam, Gavin Ha, Maria Tretiakova, Michael Haffner, and Ruben Raychaudhuri contributed to this research.

The spotlighted research was funded by the National Institutes of Health, The U.S. Department of Defense, the Doris Duke Charitable Foundation, the V Foundation, the Prostate Cancer Foundation, and the National Research Foundation of Korea.

Lee HJ, Gulati R, Sayar E, Patel RA, Itagi P, Richards HM, Persse T, Arora S, Coleman I, Adil M, Schuster SL, Shokri F, Wright JL, Yu EY, True LD, Chambers M, Hawley JE, Cheng HH, Schweizer MT, Grivas P, Nelson PS, Montgomery RB, Hsieh AC, Vakar-Lopez F, Morrissey C, Lam H, Ha G, Tretiakova MS, Haffner MC, Raychaudhuri R. 2025. Patterns of HER2 Expression in Metastatic Prostate and Urothelial Cancers: Implications for HER2-Targeted Therapies. Cancer Research Communications. doi: 10.1158/2767-9764.CRC-25-0069