Characterization of HER2 expression in prostate cancer compared with other solid tumors.

255 Background: Recent reports of promising responses to the human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing prostate cancer (PCa) (PMID: 39496182, 40638235) have prompted a clinical trial (CaRPET; NCT06610825) to evaluate T-DXd for the treatment of HER2-expressing metastatic castration-resistant PCa. HER2 expression by immunohistochemistry (IHC) is commonly observed in PCa in the absence of HER2 gene amplification, but reported rates vary due to inconsistent scoring. To address these challenges and better define the HER2 landscape in PCa, we performed a multi-platform analysis of HER2 expression using IHC, quantitative RT-PCR (qRT-PCR), and RNA-based transcriptional profiling (qTP) across a cohort of prostate tumors. We also compared the distribution of HER2 expression in PCa to that of tumors known to respond to HER2-targeted therapy to better understand its therapeutic potential. Methods: A cohort of 51 patients with PCa were selected and representative sections of formalin-fixed paraffin-embedded tissue from core biopsies and radical prostatectomies were blindly assessed for HER2 protein and mRNA expression using IHC and qRT-PCR, respectively. Normalized HER2 mRNA expression stratified by IHC scores was compared to a cohort of non- HER2 amplified breast cancer (BCa). Tumor-type distributions of HER2 RNA expression in non-amplified HER2 -expressing tumors from the Strata Select v4 pan-cancer dataset (n=12,155 tumors, 37 types) were analyzed. Results: qRT-PCR was performed for 51 patients (84% self-identified Black, 73% locally advanced, 20% metastatic) previously evaluated by HER2 IHC (IHC 0, 1+, 2+, 3+; n = 7, 20, 18, 6). The distribution of HER2 mRNA expression in PCa with IHC 0+ and IHC 1-3+ was most similar to that of BCa IHC 1+ and IHC 2+ respectively by Kolmogorov–Smirnov testing. In the Strata Select v4 cohort, PCa had the fifth highest median HER2 mRNA expression, between BCa (3rd) and non-small cell lung cancer (NSCLC) (7th), overall most resembling NSCLC (Jensen-Shannon Divergence 0.016). Conclusions: PCa exhibits HER2 expression by IHC, qRT-PCR, and qTP comparable to other tumors known to be responsive to anti-HER2 therapy. Integration of predictive biomarkers for ADC response with data from the CaRPET trial will help better understand the treatment response to HER2-targeting ADCs in PCa.