Abstract 7469: Molecular insights and biology of low-PSA high-risk prostate cancer

Abstract Background: Aggressive prostate cancer (PCa) often progresses to castration-resistant disease (CRPC), which becomes incurable and lethal. Although most PCa tumors are initially responsive to androgen deprivation therapy (ADT), duration of this response varies, and relapse typically occurs as disease transitions to CRPC in most patients. Although there have been advancements in molecular genetics and genome sequencing, early identification of lethal versus non-lethal forms of PCa remains difficult. A substantial number of PCa patients are present with high-risk tumors that produce low levels of prostate-specific antigen (PSA) at diagnosis. Research suggests that therapeutic outcomes for these patients may be unfavorable, as they may not respond as effectively to ADT or androgen receptor pathway inhibitors (ARPI). As a result, this high-risk PCa with low PSA secretion may represent an understudied subtype of the disease. Methods: Between 2013 and 2023, a total of 3619 PCa patients underwent robotic-assisted radical prostatectomy (RARP). Patients were divided into four groups based on PSA levels: very low (<2.5 ng/ml), low (2.6-5.0 ng/ml), medium (5.1-8.0 ng/ml), and high (>8.0 ng/ml). ANOVA and Pearson’s chi-squared tests were performed to compare clinical characteristics among these groups. In addition, gene expression profiles from TCGA PCa cohort were analyzed to assess differential PSA/KLK3 mRNA expression within cancer cells. To further investigate, single-cell clones from LNCaP parental population were selected to study molecular characteristics of tumor cells with low PSA expression. Results: We observed that patients with high-risk PCa and very low PSA levels (<2.5 ng/ml) experienced higher rates of biochemical recurrence than those with high-grade cancer who had PSA levels above 2.5 ng/ml. Furthermore, we observed a significantly higher occurrence of seminal vesicle invasion (p=1.058e-05) and neurovascular invasion (p=0.0047) in both very low and high PSA groups compared to other two groups. Notably, very low PSA group showed a higher rate of lymph node invasion (p=0.00095) than other three groups. Transcriptomic analysis of TCGA cohort showed genes upregulated in very low PSA group compared to high PSA group, were significantly enriched (p<0.001) in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, our study of LNCaP-derived naturally occurring low-PSA clones demonstrated enhanced migratory potential and higher expression of EMT markers compared to parental LNCaP cells, which express high levels of PSA. Conclusions: Our study reveals a distinct subtype of localized PCa characterized by low PSA levels while still displaying high-risk features. This subtype is particularly invasive and linked to potentially poor outcomes, highlighting the necessity for further investigation to gain deeper understanding of its aggressive biology and characteristics that remain largely unexplored. Citation Format: Nabila Zaman, Adriana M. Pedraza, Sarah Ann King, Prathiksha Prabhakaraalva, Natasha Kyprianou, Ashutosh K. Tewari, Goutam Chakraborty. Molecular insights and biology of low-PSA high-risk prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7469.