Abnormalities in HER2 are well-established oncogenic drivers and are approved therapeutic targets in various malignancies. Prior studies evaluating HER2 expression in prostate cancer (PCa) have yielded variable results. Most of these studies used immunohistochemistry scoring systems based on breast cancer data. The goal of this study was to determine the prevalence and clinical significance of HER2 expression using a scoring system that better reflects the HER2 staining pattern observed in PCa. We randomly selected similar numbers of localized low risk (AJCC stage I), locally advanced (AJCC stages II & III), and metastatic (AJCC stage IV) PCa patients treated at the DC VA Medical Center between 2000 and 2022. Among them, we included patients who had sufficient PCa tissue samples and clinical information required for this analysis. Two experienced pathologists independently scored HER2 expression (Ventana Pathway anti-HER2) according to a modified gastric cancer HER2 scoring system. Out of the 231 patients included, 85 % self-identified as Black. 58.9 % of patients expressed HER2 (1+: 35.5 %; 2+: 18.2 %; 3+: 5.2 %). Validity of the results was confirmed using the HercepTest antibody. Higher HER2 expression was associated with a higher Gleason Score/Grade Group and advanced disease. Our findings support the adverse prognostic impact on HER2 in PCa. We propose the use of a modified scoring system to evaluate HER2 expression in PCa. The observed high prevalence of HER2 expression supports the consideration of novel HER2-targeted therapies addressing even low levels of HER2 expression in future PCa trials.

Human Epidermal Growth Factor Receptor 2 (HER2) is expressed in approximately 60%-70% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may contribute to androgen resistance. This case report describes a patient with HER2-expressing mCRPC who progressed on multiple lines of therapy and subsequently had a significant response to combination treatment with the HER2-targeting antibody-drug-conjugate (ADC) trastuzumab deruxtecan (T-DXd) and re-­challenge of abiraterone, despite having progressed on this prior. Unlike other HER2-expressing malignancies, HER2 overexpression in prostate cancer (PCa) occurs in the absence of HER2 mutations and amplifications and, as such, is not detected by next-­generation sequencing. Therefore, identifying patients with mCRPC who could benefit from T-DXd necessitates HER2 testing by immunohistochemistry (IHC), a practice not routinely performed. As a result, T-DXd remains underutilized in patients with mCRPC, despite a tumor-agnostic approval for patients with advanced HER2-expressing (IHC 3+) solid tumors. This case highlights the potential of combining T-DXd with androgen receptor pathway inhibitors to overcome treatment resistance and underscores the importance of routine HER2 IHC testing in patients with advanced PCa.

Ductal adenocarcinoma of the prostate (DAP) is an uncommon variant of prostate cancer associated with aggressive disease and poor outcome. It presents most frequently as a mixed tumor combined with acinar adenocarcinoma. Although the histopathological features of DAP are well known, its genomic characteristics are still evolving, prompting the suggestion that all DAP would benefit from molecular analysis with the purpose of improving tumor recognition, genetic classification, and, ultimately, personalized therapy. Herein, we report a case of DAP with novel genetic alterations (BCOR P1153S, ERG M219I, KDR A750E, POLE S1896P, and RAD21 T461del).

Background: Next-generation sequencing has revealed TP53 alterations in localized prostate cancer (PCa), suggesting growing clinical potential for p53 immunohistochemistry (IHC). Prior research supports the use of IHC for the detection of p53 overexpression to predict the presence of TP53 alterations known to be associated with adverse outcomes. However, to reach a consensus definition of p53 overexpression in PCa, further insights are needed. This study aimed to compare two fundamental approaches of evaluating p53 expression across a variety of specimens regarding PCa progression. Methods: This study included 84 patients (75% self-identified as African American) diagnosed with PCa between 1996 and 2021 at the DC VA Medical Center. Representative sections of core biopsies, radical prostatectomies, transurethral prostate resections, and metastatic deposits were examined. p53 nuclear expression was scored according to the highest intensity observed (0, 1+, 2+, 3+) and the percentage (0%, 5%) of tumor cells expressing any level of intensity in the aggregate tumor area. All slides were reviewed by two independent pathologists. Pertinent clinical data were collected. Results: A total of 34 patients (40%) exhibited p53 nuclear expression, of which 18 (21%) showed the maximum (3+) intensity. The presence of maximum intensity, regardless of percentage, was found to be associated with Grade Group (p < 0.001), higher PSA at biopsy (p < 0.001), BCR (p < 0.001) and metastasis (p < 0.001). Importantly, maximum p53 intensity was identified only in patients who developed metastatic disease. Conclusions: Maximum (3+) p53 nuclear intensity of any percentage is highly associated with disease progression in PCa, suggesting that optimal determination of p53 overexpression should incorporate intensity.

Noncoding RNAs (ncRNAs) defy the central dogma by representing a family of RNA molecules that are not translated into protein but can convey information encoded in their DNA. Elucidating the exact function of ncRNA has been a focus of discovery in the last decade and remains challenging. Nevertheless, the importance of understanding ncRNA is apparent since these molecules regulate gene expression at the transcriptional and post-transcriptional level exerting pleiotropic effects critical in development, oncogenesis, and immunity. NcRNAs have been referred to as “the dark matter of the nucleus”, and unraveling their role in physiologic and pathologic processes will provide vast opportunities for basic and translational research with the potential for significant therapeutic progress. Consequently, strong efforts are underway to exploit the therapeutic utility of ncRNA, some of which have been approved by the US Food and Drug Administration and the European Medicines Agency. The use of ncRNA therapeutics (or “vaccines” if defined as anti-disease agents) may result in improved curative strategies when used alone or in combination with existing treatments. This review will focus on the role of ncRNA therapeutics in prostatic carcinoma while exploring basic biological aspects of these molecules that represent about 97% of the transcriptome in humans.