Molecular insights of low-PSA–expressing high-risk prostate cancer.

416 Background: Despite advances in molecular genetics and genome sequencing, identifying lethal and non-lethal forms of prostate cancer in the early stages of the disease remains challenging. A significant number of prostate cancer patients have high-risk tumors that produce low levels of prostate-specific antigen (PSA) at the time of diagnosis. There is an indication that the therapeutic outcome of these patients, may be considered unfavorable as they may not respond as well to ADT or androgen receptor pathway inhibitors (ARPI). Consequently, this type of high-risk prostate cancer with low PSA secretion may be associated with a unique subtype of the disease that has not been fully characterized. Methods: From 2013 to 2023, 3,619 patients diagnosed with prostate cancer underwent robotic-assisted radical prostatectomy (RARP) performed by a single experienced surgeon (AKT). The patients were classified into four groups based on their 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). We conducted an ANOVA analysis to compare various clinical characteristics across these groups. Additionally, we explored the gene expression profiles from the Cancer Genome Atlas (TCGA) prostate cancer cohort, specifically examining differential PSA/KLK3 mRNA expression within cancer cells. Furthermore, we selected and expanded single-cell clones from the LNCaP parental population to investigate the molecular landscape of low PSA expressing prostate tumor cells. Results: We observed that patients with high-risk prostate cancer and a very low PSA level (<2.5 ng/ml) had higher rates of biochemical recurrence compared to those with high-grade cancer but PSA levels (>2.5 ng/ml). Additionally, we noticed a significantly high presence of seminal vesicle (p= 1.058e-05) and neurovascular invasion (p=0.0047) in both the very low and high PSA groups compared to the other two groups. Importantly, the very low PSA group exhibited a higher rate of lymph node invasion (p= 0.00095) compared to the other three groups. Our transcriptomic analysis in the TCGA cohort revealed that genes which are upregulated in the very low PSA group compared to the high PSA group are significantly (p<0.001) enriched in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, our study on LNCaP-derived clones revealed an increased migration potential and elevated expression of mesenchymal markers in LNCaP-PSA Low clones compared to the clones expressing high PSA. Conclusions: Our research identifies a distinct subtype of localized prostate cancer, demonstrating that low-PSA, high-risk prostate cancer is significantly invasive and leads to potentially lethal disease. This highlights the need for further investigation to better understand the biology of this poorly defined but aggressive subtype of localized prostate cancer.