Abstract B036: Molecular drivers of biochemical recurrence post radical prostatectomy among men with prostate cancer

Abstract Leveraging unsupervised clustering to capture transcriptomic variation and map temporal dynamics in disease progression provides a framework for linking molecular biology to heterogeneous clinical phenotypes. Radical prostatectomy (RP) or radiation therapy are standard treatments for localized prostate cancer (PCa), yet up to ∼15-30% of men experience a rise in blood prostate-specific antigen (PSA) levels (termed biochemical recurrence; BCR) after definitive local therapies for curative intent, reflecting potential disease recurrence. BCR represents a spectrum of disease states with varying implications for subsequent radiographic and/or clinical progression, reflecting the complex underlying tumor biology of PCa. The time until a patient experiences a post-RP rise in PSA—termed time to biochemical recurrence (tBCR)—is an important marker as it can provide insights into risk for clinical progression. The molecular drivers of the BCR disease state are not clearly defined, which is necessary to better understand drivers of recurrence and optimize management of this population of patients. Our initial study has examined transcriptomic data from 501 patients in the TCGA Prostate Adenocarcinoma dataset who underwent RP, of which 74 experienced BCR. Patients with BCR were stratified into quartiles by “Days to BCR” and their gene expression profiles were analyzed using Gene Set Variation Analysis, K-means Clustering, Principal Component Analysis (PCA), and Over-Representation Analysis (ORA). Further, disease free survival (DFS) and overall survival (OS) were assessed to determine clinical relevance of identified disease signatures. Notably, K-means clustering identified a distinct 95-gene cluster showing a linear increase in gene expression that stratifies early from late and never recurrent groups. PCA was subsequently used to identify the top 10 contributing genes to this linearity. Overexpression of epithelial splicing regulatory protein 1 (ESRP1), a regulator of epithelial-mesenchymal transition, accounted for the most variance in the principal component and was found to be significantly associated with early recurrence, as well as decreased DFS and OS in both the TCGA and in an independent metastatic prostate cancer dataset. Additionally, ORA identified a 26-gene signature related to immune cells, i.e., tumor-associated macrophages (TAMs), dendritic cells (DCs), and natural killer (NK) cells, with a 6-gene subset common to all three immune cell types. This 6-gene signature was also associated with early recurrence and DFS/OS in two independent datasets. Analysis of clinical genomic, transcriptomic, and outcomes data for localized and metastatic disease confirmed that K-means clustering effectively separated patients by tBCR via unique transcriptomic signatures, identifying signatures that predict poor prognoses in independent PCa datasets, and suggest modulation of EMT processes and perturbation of immune cell populations in patients who experience early biochemical recurrence. Citation Format: Zumar Meher, Safiullah Rifai, Azimullah Rifai, Tausif Khan, Wei Guang, Mohamad Khan, Arif Hussain. Molecular drivers of biochemical recurrence post radical prostatectomy among men with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B036.