Andrew W Hahn1, David M Gill1, Roberto H Nussenzveig1, Austin Poole1, Jim Farnham2, Lisa Cannon-Albright2, Neeraj Agarwal3. 1. Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. 2. Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT. 3. Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. Electronic address: neeraj.agarwal@hci.utah.edu.
Abstract
BACKGROUND: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. METHODS: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA. RESULTS: Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA. CONCLUSION: The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.
BACKGROUND: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer. METHODS: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA. RESULTS: Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA. CONCLUSION: The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.
Authors: Elahe A Mostaghel; Brett T Marck; Orpheus Kolokythas; Felix Chew; Evan Y Yu; Michael T Schweizer; Heather H Cheng; Phillip W Kantoff; Steven P Balk; Mary-Ellen Taplin; Nima Sharifi; Alvin M Matsumoto; Peter S Nelson; R Bruce Montgomery Journal: Clin Cancer Res Date: 2021-08-18 Impact factor: 12.531
Authors: Mohammad Alyamani; Hamid Emamekhoo; Sunho Park; Jennifer Taylor; Nima Almassi; Sunil Upadhyay; Allison Tyler; Michael P Berk; Bo Hu; Tae Hyun Hwang; William Douglas Figg; Cody J Peer; Caly Chien; Vadim S Koshkin; Prateek Mendiratta; Petros Grivas; Brian Rini; Jorge Garcia; Richard J Auchus; Nima Sharifi Journal: J Clin Invest Date: 2018-06-25 Impact factor: 14.808