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Brief Report
October 12, 2017

HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer

Author Affiliations
  • 1Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
  • 2Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
  • 3Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco
  • 4Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
  • 5Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
JAMA Oncol. Published online October 12, 2017. doi:10.1001/jamaoncol.2017.3159
Key Points

Question  Is inheritance of the HSD3B1 (1245C) genotype that encodes for a gain-of-function in 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1) and an increase in potent androgen synthesis from extragonadal precursor steroids associated with more favorable treatment outcomes with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition among men with metastatic castration-resistant prostate cancer (CRPC)?

Findings  In this study of 90 men with metastatic CRPC, the presence of the HSD3B1 (1245C) variant allele was associated with increased duration of therapy and increased progression-free survival with ketoconazole treatment.

Meaning  HSD3B1 (1245C) inheritance, which is a known predictive biomarker of resistance to castration, is also predictive of response to nonsteroidal CYP17A1 inhibition, identifying a subset of tumors that are clinically more dependent on extragonadal precursor steroids.

Abstract

Importance  The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC).

Objective  To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC.

Design, Setting, and Participants  An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco.

Exposures  Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC.

Main Outcomes and Measures  The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype.

Results  A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03).

Conclusions and Relevance  Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.

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