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HSD3B1 Allele May Be Associated With Resistance to Androgen-Deprivation Therapy and Poorer Outcome in Prostate Cancer

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Key Points

  • The HSD3B1 (1245C) allele was associated with poorer progression-free survival in men with prostate cancer.
  • Outcome was poorest in men with the heterozygous variant genotype.

In a retrospective multicohort study reported in The Lancet Oncology, Hearn et al found that the inherited HSD3B1 (1245C) allele was significantly associated with resistance to androgen-deprivation therapy and poorer outcome in men with prostate cancer. HSD3B1 (1245A>C) has been linked to castration-resistant prostate cancer via its activity in encoding an altered enzyme that increases synthesis of dihydrotestosterone from nongonadal precursors.

Study Details

In the study, HSD3B1 genotype was determined retrospectively in men treated with androgen-deprivation therapy for postprostatectomy biochemical failure, and genotype was correlated with long-term clinical outcome. Data and samples were from prospectively maintained registries at the Cleveland Clinic (primary study cohort) and the Mayo Clinic, Rochester (postprostatectomy and metastatic validation cohorts).

Patients in the postprostatectomy cohorts underwent prostatectomy between January 1996 and December 2009 at the Cleveland Clinic or between January 1987 and December 2011 at the Mayo Clinic and received androgen-deprivation therapy for biochemical failure or nonmetastatic clinical failure. Patients in the metastatic validation cohort were enrolled between September 2009 and July 2013 with metastatic castration-resistant prostate cancer. The primary endpoint was progression-free survival according to the HSD3B1 genotype.

Outcomes in Primary Cohort

Overall, 443 patients were genotyped, including 118 in the primary cohort, 137 in the postprostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary cohort, 37% of patients were homozygous wild-type, 53% were heterozygous variant, and 10% were homozygous variant. Median progression-free survival according to the number of HSD3B1 (1245C) variant alleles was 6.6 years for homozygous wild-type, 4.1 years for heterozygous variant (hazard ratio [HR] = 2.4, P = .029), and 2.5 years for homozygous variant (HR = 1.7, P = .041; P = .011 overall).

Validation Cohorts

In the postprostatectomy validation cohort, 56% of patients were homozygous wild-type, 37% were heterozygous variant, and 7% were homozygous variant. Median progression-free survival was 3.3 years for homozygous wild-type, 2.8 years for heterozygous variant (HR = 1.0, P = .85), and 0.9 years for homozygous variant (HR = 3.4, P = .0013).

In the metastatic validation cohort, 52% of patients were homozygous wild-type, 42% were heterozygous variant, and 6% were homozygous variant. Median progression-free survival was 1.8 years for homozygous wild-type, 1.4 years for heterozygous variant (HR = 1.1, P = .38), and 0.8 years for heterozygous variant (HR = 2.0, P = .027). Similar results were observed for distant metastasis–free survival and overall survival.

The investigators concluded: “Inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to [androgen-deprivation therapy]. HSD3B1 could therefore potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with [androgen-deprivation therapy] from those who harbour disease liable to behave more aggressively and who therefore might warrant early escalated therapy.”

The study was funded by the Prostate Cancer Foundation, National Institutes of Health, U.S. Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Conquer Cancer Foundation of ASCO, Cleveland Clinic Research Programs Committee and Department of Radiation Oncology, and Gail and Joseph Gassner Development Funds.

Nima Sharifi, MD, of Lerner Research Institute, Cleveland Clinic, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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