title: HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study.
abstract: BACKGROUND
  HSD3B1 (1245A>C) has been mechanistically linked to castration-resistant prostate cancer because it encodes an altered enzyme that augments dihydrotestosterone synthesis from non-gonadal precursors. We postulated that men inheriting the HSD3B1 (1245C) allele would exhibit resistance to androgen-deprivation therapy (ADT).
  
  
  METHODS
  In this multicohort study, we determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. We used data and samples from prospectively maintained prostate cancer registries at the Cleveland Clinic (Cleveland, OH, USA; primary study cohort) and the Mayo Clinic (Rochester, MN, USA; post-prostatectomy and metastatic validation cohorts). In the post-prostatectomy cohorts, patients of any age were eligible if they underwent prostatectomy between Jan 1, 1996, and Dec 31, 2009 (at the Cleveland Clinic; primary cohort), or between Jan 1, 1987, and Dec 31, 2011 (at the Mayo Clinic; post-prostatectomy cohort) and were treated with ADT for biochemical failure or for non-metastatic clinical failure. In the metastatic validation cohort, patients of any age were eligible if they were enrolled at Mayo Clinic between Sept 1, 2009, and July 31, 2013, with metastatic castration-resistant prostate cancer. The primary endpoint was progression-free survival according to HSD3B1 genotype. We did prespecified multivariable analyses to assess the independent predictive value of HSD3B1 genotype on outcomes.
  
  
  RESULTS
  We included and genotyped 443 patients: 118 in the primary cohort (who underwent prostatectomy), 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median progression-free survival diminished as a function of the number of variant alleles inherited: 6·6 years (95% CI 3·8-not reached) in men with homozygous wild-type genotype, 4·1 years (3·0-5·5) in men with heterozygous variant genotype, and 2·5 years (0·7 to not reached) in men with homozygous variant genotype (p=0·011). Relative to the homozygous wild-type genotype, inheritance of two copies of the variant allele was predictive of decreased progression-free survival (hazard ratio [HR] 2·4 [95% CI 1·1-5·3], p=0·029), as was inheritance of one copy of the variant allele (HR 1·7 [1·0-2·9], p=0·041). Findings were similar for distant metastasis-free survival and overall survival. The effect of the HSD3B1 genotype was independently confirmed in the validation cohorts.
  
  
  CONCLUSIONS
  Inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. HSD3B1 could therefore potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with ADT from those who harbour disease liable to behave more aggressively, and who therefore might warrant early escalated therapy.
  
  
  BACKGROUND
  Prostate Cancer Foundation, National Institutes of Health, US Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Conquer Cancer Foundation of the American Society of Clinical Oncology, Cleveland Clinic Research Programs Committee and Department of Radiation Oncology, Gail and Joseph Gassner Development Funds.
authors: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland, OH, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
authors: Jason W D
authors: JWD
authors: Hearn
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
authors: Ghada
authors: G
authors: AbuAli
authors: Department of Urology, Glickman Urological & Kidney Institute, Cleveland, OH, USA.
authors: Chad A
authors: CA
authors: Reichard
authors: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland, OH, USA.
authors: Chandana A
authors: CA
authors: Reddy
authors: RT Pathology and Laboratory Medicine Institute, Cleveland, OH, USA.
authors: Cristina
authors: C
authors: Magi-Galluzzi
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
authors: Kai-Hsiung
authors: KH
authors: Chang
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Rachel
authors: R
authors: Carlson
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Laureano
authors: L
authors: Rangel
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors: Kevin
authors: K
authors: Reagan
authors: Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
authors: Brian J
authors: BJ
authors: Davis
authors: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors: R Jeffrey
authors: RJ
authors: Karnes
authors: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors: Manish
authors: M
authors: Kohli
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors: Donald
authors: D
authors: Tindall
authors: Department of Urology, Glickman Urological & Kidney Institute, Cleveland, OH, USA.
authors: Eric A
authors: EA
authors: Klein
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA; Department of Urology, Glickman Urological & Kidney Institute, Cleveland, OH, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: sharifn@ccf.org.
authors: Nima
authors: N
authors: Sharifi
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011375:Progesterone Reductase / Q000235:genetics*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D012189:Retrospective Studies; D013251:Steroid Isomerases / Q000235:genetics*
chemical_list: C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D000726:Androgen Antagonists; D009097:Multienzyme Complexes; D011375:Progesterone Reductase; D013251:Steroid Isomerases