362 - Influence of HSD3B1 Genotype on Prostate Cancer Outcomes following Definitive Radiation Therapy with Androgen Deprivation Therapy: A Retrospective Analysis of the Million Veterans Program
Presenter(s)
K. M. Morgan1,2, C. Teerlink3, T. J. Nelson1, K. M. Lee4, T. M. Seibert5, R. R. Mckay6, J. A. Lynch7, R. Hauger8, and B. S. Rose2; 1VA San Diego Health Care System, La Jolla, CA, 2Department of Radiation Medicine and Applied Sciences, UC San Diego Health, San Diego, CA, 3Veteran Affairs Medical Center, Salt Lake City, UT, 4VA Informatics and Computing Infrastructure, Salt Lake City, UT, 5Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 6University of California San Diego, La Jolla, CA, 7Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 8UC San Diego Department of Psychiatry, La Jolla, CA
Purpose/Objective(s): The adrenal-permissive HSD3B1(1245C) allele has been associated with resistance to androgen deprivation therapy (ADT) leading to poorer outcomes in men with advanced prostate cancer. Whether HSD3B1 genotype affects curative therapy outcomes for men undergoing radiotherapy with ADT is unknown. We tested the hypothesis that men with adrenal permissive HSD3B1 genotype will have poorer outcomes when undergoing ADT.
Materials/Methods: This study analyzed patients from the Million Veterans Program (MVP) within the Veterans Health Administration (VHA) database utilizing Veterans Informatics and Computing Infrastructure (VINCI). Eligible patients were diagnosed with localized prostate cancer (PCa) after MVP enrollment and received definitive radiation therapy with ADT. HSD3B1 genotype status was categorized as homozygous adrenal-restrictive (AA), heterozygous adrenal-restrictive (AC), or homozygous adrenal-permissive (CC). The primary outcomes of interest included biochemical recurrence (BCR), metastatic castration-resistant prostate cancer (MCRPC), and cancer-specific mortality (CSM), identified using the National Death Index (NDI). NDI data was available through 12/31/2021, after which all patients with continued follow-up were censored for the CSM analysis. Cox proportional hazard models were applied to examine the associations between HSD3B1 genotype and outcomes of interest, adjusting for relevant clinical factors, including cancer staging, demographic characteristics, and treatment details. Time-to-event analyses were performed from the date of PCa diagnosis to the outcome of interest.
Results: Of the 3,170 participants included in the study, 209 (6.6 %) had the CC genotype, 1105 (34.9 %) had the AC genotype, and 1866 (58.5 %) had the AA genotype. Patients with the CC genotype demonstrated an increased risk of BCR (HR, 1.91; 95% CI, 1.27-2.86; P =0.0018) and progression to MCRPC (HR, 1.84; 95% CI, 1.05-3.19; P=0.03) compared to those with the AC/AA genotypes. The CC genotype had a HR of 1.87 for CSM compared to the AC/AA genotypes (P = 0.09).
Conclusion: In this large cohort of US veterans undergoing treatment for localized prostate cancer, the HSD3B1 CC genotype was associated with inferior oncologic outcomes following definitive radiation therapy with ADT. These findings support the potential utility of HSD3B1 as a predictive biomarker for treatment response and underscore the need for therapeutic strategies targeting 3ß-hydroxysteroid dehydrogenase-1 and the androgen-signaling axis to improve outcomes in this high-risk population.