HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study

Jason W D Hearn, Ghada AbuAli, Chad A. Reichard, Chandana A. Reddy, Cristina Magi-Galluzzi, Kai Hsiung Chang, Rachel Carlson, Laureano Rangel, Kevin Reagan, Brian J. Davis, R. Jeffrey Karnes, Manish Kohli, Donald Tindall, Eric A. Klein, Nima Sharifi

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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. Findings 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. Interpretation 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. Funding 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.

Original languageEnglish (US)
Pages (from-to)1435-1444
Number of pages10
JournalThe Lancet Oncology
Volume17
Issue number10
DOIs
StatePublished - Oct 1 2016

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Androgens
Prostatic Neoplasms
Prostatectomy
Retrospective Studies
Genotype
Alleles
Disease-Free Survival
Therapeutics
Dihydrotestosterone
Castration
Cohort Studies
Radiation Oncology
Survival
National Institutes of Health (U.S.)
Financial Management
Secondary Prevention
Registries
Biomarkers
Neoplasm Metastasis
Enzymes

ASJC Scopus subject areas

  • Oncology

Cite this

Hearn, J. W. D., AbuAli, G., Reichard, C. A., Reddy, C. A., Magi-Galluzzi, C., Chang, K. H., ... Sharifi, N. (2016). HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. The Lancet Oncology, 17(10), 1435-1444. https://doi.org/10.1016/S1470-2045(16)30227-3

HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer : a retrospective, multicohort study. / Hearn, Jason W D; AbuAli, Ghada; Reichard, Chad A.; Reddy, Chandana A.; Magi-Galluzzi, Cristina; Chang, Kai Hsiung; Carlson, Rachel; Rangel, Laureano; Reagan, Kevin; Davis, Brian J.; Karnes, R. Jeffrey; Kohli, Manish; Tindall, Donald; Klein, Eric A.; Sharifi, Nima.

In: The Lancet Oncology, Vol. 17, No. 10, 01.10.2016, p. 1435-1444.

Research output: Contribution to journalArticle

Hearn, JWD, AbuAli, G, Reichard, CA, Reddy, CA, Magi-Galluzzi, C, Chang, KH, Carlson, R, Rangel, L, Reagan, K, Davis, BJ, Karnes, RJ, Kohli, M, Tindall, D, Klein, EA & Sharifi, N 2016, 'HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study', The Lancet Oncology, vol. 17, no. 10, pp. 1435-1444. https://doi.org/10.1016/S1470-2045(16)30227-3
Hearn, Jason W D ; AbuAli, Ghada ; Reichard, Chad A. ; Reddy, Chandana A. ; Magi-Galluzzi, Cristina ; Chang, Kai Hsiung ; Carlson, Rachel ; Rangel, Laureano ; Reagan, Kevin ; Davis, Brian J. ; Karnes, R. Jeffrey ; Kohli, Manish ; Tindall, Donald ; Klein, Eric A. ; Sharifi, Nima. / HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer : a retrospective, multicohort study. In: The Lancet Oncology. 2016 ; Vol. 17, No. 10. pp. 1435-1444.
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T1 - HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer

T2 - a retrospective, multicohort study

AU - Hearn, Jason W D

AU - AbuAli, Ghada

AU - Reichard, Chad A.

AU - Reddy, Chandana A.

AU - Magi-Galluzzi, Cristina

AU - Chang, Kai Hsiung

AU - Carlson, Rachel

AU - Rangel, Laureano

AU - Reagan, Kevin

AU - Davis, Brian J.

AU - Karnes, R. Jeffrey

AU - Kohli, Manish

AU - Tindall, Donald

AU - Klein, Eric A.

AU - Sharifi, Nima

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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. Findings 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. Interpretation 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. Funding 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.

AB - 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. Findings 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. Interpretation 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. Funding 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.

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