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SUO 2017

SUO 2017: Alterations in Steroid Metabolism and AR Responsiveness

Washington, DC (UroToday.com) Dr. Sharifi provided a discussion of the alterations of steroid metabolism and androgen receptor (AR) responsiveness. Dr. Sharifi started by stating that steroid metabolism is a major regulator of clinical outcomes in prostate cancer, regulated by a key enzyme: 3ß-hydroxysteroid dehydrogenase (3ßHSD), which controls DHEA à androstenedione. Downstream, this affects synthesis of dihydrotestosterone (DHT). However, a gain-of-function point mutation in 3ßHSD1 accounts for increased enzymatic activity and DHT protein levels in castration-resistant prostate cancer 1.

Does the 3ßHSD1 germline variant regulate the variability in response to ADT? In Dr. Sharifi’s opinion, there is an additive-effect for additional 3ßHSD1 variant mutations leading to increased resistant to ADT with each mutation. Furthermore, this theory appears to have clinical significance. In men with CRPC, progression free-survival was 6.6 years for the homozygous WT gene, compared to 4.1 years for the 3ßHSD1 heterozygous mutation and 2.5 years for 3ßHSD1 homozygous variants 2. These results were also validated in a separate cohort3.

Subsequently, Dr. Sharifi’s group assessed whether the variant 3ßHSD1 (1245C) allele predicted resistance to ADT for biochemically recurrent prostate cancer after radiotherapy4. In a study of 213 patients, increasing number of variant alleles was associated with poorer metastasis free survival, however there was no impact on overall survival. Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor antagonist during salvage treatment, both of which may attenuate the effect of the variant allele.

Dr. Sharifi concluded with several take-home points from his presentation:
  • 3ßHSD1 missense mutation increases metabolic flux to DHT in CRPC à this may act as a predictive biomarker of resistant to ADT
  • 3ßHSD1 may act as a germline predictive biomarker of sensitivity to CYP17A1 inhibition
  • Carriers of the missense mutation make more of an abiraterone metabolite with AR agonist activity
References:
  1. Chang KH, Li R, Kuri B, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 2013;154(5):1074-1084.
  2. Hearn JWD, AbuAli G, Reichard CA, et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol 2016;17(10):1435-1444.
  3. Agarwal N, Hahn AW, Gill DM, et al. JAMA Oncol 2017;3(6):856-857.
  4. Hearn JWD, Xie W, Nakabayashi M, et al. Association of HSDB1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol 2017 Oct 12 [Epub ahead of print].
Presented by: Nima Sharifi, Cleveland Clinic Foundation, Cleveland, OH

Written by: Zachary Klaassen, MD, Society of Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC