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Figure.
Kaplan-Meier Curve of Progression-Free Survival by Number of HSD3B1 Variants
Kaplan-Meier Curve of Progression-Free Survival by Number of HSD3B1 Variants

Data adjusted for Gleason score and log prostate-specific antigen level.

Table.  
Baseline Characteristics of the Primary Cohort by HSD3B1 Genotype
Baseline Characteristics of the Primary Cohort by HSD3B1 Genotype
1.
Hearn  JW, 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.PubMedGoogle ScholarCrossref
2.
Simard  J, Ricketts  ML, Gingras  S, Soucy  P, Feltus  FA, Melner  MH.  Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family.  Endocr Rev. 2005;26(4):525-582.PubMedGoogle ScholarCrossref
3.
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.PubMedGoogle ScholarCrossref
4.
Scher  HI, Halabi  S, Tannock  I,  et al; Prostate Cancer Clinical Trials Working Group.  Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.  J Clin Oncol. 2008;26(7):1148-1159. doi:10.1200/JCO.2007.12.4487PubMedGoogle ScholarCrossref
Research Letter
June 2017

Independent Validation of Effect of HSD3B1 Genotype on Response to Androgen-Deprivation Therapy in Prostate Cancer

Author Affiliations
  • 1University of Utah Huntsman Cancer Institute, Salt Lake City
  • 2Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City
JAMA Oncol. 2017;3(6):856-857. doi:10.1001/jamaoncol.2017.0147

Substantial advances have been made in the development of therapeutic biomarkers in various cancers, but not in prostate cancer. A germline inherited polymorphic variant (1245A→C) in the HSD3B1 gene was recently reported to correlate with shorter duration of response to androgen-deprivation therapy (ADT) in hormone-sensitive prostate cancer (HSPC).1 The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen.2,3 In the study by Hearn et al,1 presence of 1 or more variant alleles of the HSD3B1 (1245C) was associated with decreased progression-free survival (PFS) compared with the absence of any variant alleles in 3 cohorts of men with prostate cancer treated with ADT: 2 cohorts with post-prostatectomy biochemical recurrence, and 1 cohort with metastatic HSPC (mHSPC) (total, n = 443). In the present analysis, we provide, to our knowledge, the first independent validation of these results, which have the potential to introduce the first predictive biomarker of response to therapy for this patient population.

Methods

We analyzed data from a prospectively maintained prostate cancer registry to determine HSD3B1 genotype retrospectively in men treated with ADT for newly diagnosed mHSPC and to correlate this genotype with response to ADT. The study was approved by the University of Utah institutional review board. All included patients have provided their written informed consent. Genotyping was performed as described by Hearn at al.1 The primary end point was PFS on ADT. Progression was defined as 2 consecutive increases in the level of prostate-specific antigen (PSA) meeting the following criteria: 2 ng/mL or greater and 25% increase or more from the nadir, as defined by the Prostate Cancer Working Group 2,4 and/or radiographic or clinical findings of progression. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on PFS on ADT (Table).

Results

A total of 102 men diagnosed with new-onset mHSPC had all of the required clinical and genotype data available and were eligible to be included in this study. Median follow-up for this study was 35.5 months. The allelic frequency of the HSD3B1 (1245C) variant in our cohort was 31%, which is similar to that reported by Hearn et al (26%-36% in their 3 cohorts).1 In multivariate analysis controlling for Gleason score and baseline log PSA, those men in the homozygous variant group had significantly shorter median PFS than those in the homozygous wild-type group (11 vs 21 months; HR, 2.16; 95% CI, 1.01-4.58; P = .046). No significant difference in median PFS was observed between those men in the heterozygous group and those in the homozygous wild-type group (19 vs 21 months; HR, 1.04; 95% CI, 0.64-1.07; P = .86) (Table). The Figure shows a Kaplan-Meier curve of PFS by the number of HSD3B1 variants present while controlling for Gleason score and log PSA. In comparison with the metastatic cohort reported by Hearn et al,1 the prevalence of homozygosity for the variant allele was higher in the present study (9.8% in 102 patients vs 5.8% in 188 patients). The median PFS on ADT for the homozygous variants cohort in the present study (11.0 months) was similar to that found by Hearn et al (9.8 months). One limitation of the present study is that PFS was determined by PSA progression alone in most patients because imaging studies were not consistently performed in this real world population.

Conclusions

In this study, we independently validate that the HSD3B1 (1245C) variant allele is associated with a shorter PFS on ADT in men with mHSPC, and we confirm that the allele frequency of HSD3B1 is about 30% in this population. The 10% of men homozygous for variant allele HSD3B1 (1245C) are likely to have suboptimal response to ADT alone. These men may benefit more from up-front docetaxel treatment or from enrollment in trials investigating up-front deeper androgen blockade with novel androgen-signaling inhibitors.

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Article Information

Corresponding Author: Neeraj Agarwal, MD, University of Utah Huntsman Cancer Institute, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT 84121 (neeraj.agarwal@hci.utah.edu).

Published Online: February 16, 2017. doi:10.1001/jamaoncol.2017.0147

Author Contributions: Dr Agarwal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Agarwal, Hahn, Gill, Cannon-Albright.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Agarwal, Hahn, Gill, Farnham.

Critical revision of the manuscript for important intellectual content: Agarwal, Hahn, Gill, Poole, Cannon-Albright.

Statistical analysis: Gill, Farnham.

Obtained funding: Agarwal, Cannon-Albright.

Administrative, technical, or material support: Agarwal, Cannon-Albright.

Supervision: Agarwal, Cannon-Albright.

No additional contributions: Hahn, Poole.

Conflict of Interest Disclosures: Dr Agarwal has received research funding through the Huntsman Cancer Institute from Medivation, Janssen, and Bayer. No other conflicts are reported.

Funding/Support: This study was supported by the US Department of Defense Prostate Cancer Research Program of the Office of the Congressionally Directed Medical Research Programs, Grant No. W81XWH-11-1-0342 (Dr Cannon-Albright); and 2014 National Cancer Institute- Cancer Clinical Investigator Team Leadership Award 3P30CA042014-25S2 (Dr Agarwal).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: This paper was presented at the American Society of Clinical Oncology 2017 Genitourinary Cancers Symposium; February 16, 2017; Orlando, Florida.

References
1.
Hearn  JW, 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.PubMedGoogle ScholarCrossref
2.
Simard  J, Ricketts  ML, Gingras  S, Soucy  P, Feltus  FA, Melner  MH.  Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family.  Endocr Rev. 2005;26(4):525-582.PubMedGoogle ScholarCrossref
3.
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.PubMedGoogle ScholarCrossref
4.
Scher  HI, Halabi  S, Tannock  I,  et al; Prostate Cancer Clinical Trials Working Group.  Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.  J Clin Oncol. 2008;26(7):1148-1159. doi:10.1200/JCO.2007.12.4487PubMedGoogle ScholarCrossref
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