Abstract 1177: Prognostic implications of circulating Hepsin in prostate cancer.

Abstract Introduction and Objective: Hepsin, a type II transmembrane serine protease, has been implicated in prostate tumor progression and metastasis. Recent studies have uncovered its proteolytic auto-activation and ectodomain shedding, supporting its potential as a circulating serum biomarker. We developed a quantitative sandwich ELISA to detect non-membrane-associated (circulating) Hepsin and evaluated its clinical relevance across benign prostatic hyperplasia (BPH), primary prostate cancer, and biochemical recurrence (BCR) following radical laparoscopic prostatectomy (RALP). Methods: A proprietary ELISA was established using two monoclonal antibodies screened against ovarian ascites to identify native circulating Hepsin. Antibodies were further validated using recombinant extracellular Hepsin containing a thrombin cleavage site, mimicking auto-activation and shedding. The detection antibody was characterized via High-Mass MALDI mapping to the poorly conserved non-catalytic domain of Hepsin. Retrospective analyses were performed on data from an IRB-approved prospective study (2018-present) including 543 patients undergoing prostate evaluation, stratified by Hepsin status. Clinicopathologic variables (BPH, tumor stage, metastasis) were compared between Hepsin-positive and -negative groups using Chi-square or Fisher’s Exact tests. Among 200 RALP patients, BCR-free survival was analyzed by Kaplan-Meier and Cox regression. Results: Hepsin positivity occurred in 109 of the 543 (20%) patients. Compared to Hepsin-negative patients, positive patients showed higher cancer incidence vs BPH (p<0.05), advanced stage (≥pT3a) (p<0.05), and metastasis (p<0.05). Kaplan-Meier analysis demonstrated significantly reduced recurrence-free survival in Hepsin-positive patients (log-rank p < 0.001), with a Cox hazard ratio of 4.2 (95% CI 2.3-7.8). Notably, circulating Hepsin was determined to be an independent predictor of BCR (p = 0.0001). Furthermore, in comparison to CAPRA-S low-risk with concurrent Hepsin-negativity, Hepsin-positivity rendered an additive prognostic potential in patients with concurrent high CAPRA-S scores (p = 0.0003) compared to CAPRA-S high alone (p = 0.0007). Conclusions: This study provides early evidence regarding Hepsin's ability to identify prostate cancer patients harboring a significantly elevated risk of BCR and adverse pathology post-RALP. These data highlight a novel role for non-invasive, longitudinal evaluation of circulating Hepsin levels in the prostate cancer setting. Citation Format: Taylor Wadley, Adam Cole, Blake P. Johnson. Prognostic implications of circulating Hepsin in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1177.