Dataset Information

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

ABSTRACT: BACKGROUND:A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3?-hydroxysteroid dehydrogenase 1 (3?HSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3?HSD1 to multiple steroidal metabolites, including 3-keto-5?-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5?-abiraterone synthesis in patients. METHODS:First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5?-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS:Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5?-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION:Increased generation of 3-keto-5?-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING:Prostate Cancer Foundation Challenge Award, National Cancer Institute.

SUBMITTER: Alyamani M

PROVIDER: S-EPMC6063492 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

Alyamani Mohammad M Emamekhoo Hamid H Park Sunho S Taylor Jennifer J Almassi Nima N Upadhyay Sunil S Tyler Allison A Berk Michael P MP Hu Bo B Hwang Tae Hyun TH Figg William Douglas WD Peer Cody J CJ Chien Caly C Koshkin Vadim S VS Mendiratta Prateek P Grivas Petros P Rini Brian B Garcia Jorge J Auchus Richard J RJ Sharifi Nima N

The Journal of clinical investigation 20180625 8

<h4>Background</h4>A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from ...[more]

PMID: 29939161

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Project description:ImportanceRecently, genetic polymorphism in HSD3B1 encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear.ObjectiveTo investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone.Design, setting, and participantsThis prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing.ExposuresPrimary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer.Main outcomes and measuresThe association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined.ResultsOf 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49; P = .03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69; P = .006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94; P = .04) compared with men carrying homozygous wild type.Conclusions and relevanceThis study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.

Project description:ImportanceThe adrenal androgen-metabolizing 3β-hydroxysteroid dehydrogenase-1 enzyme, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary for synthesizing nontesticular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding the 3β-HSD1 protein with decreased susceptibility to degradation resulting in higher extragonadal androgen synthesis. Retrospective studies have suggested an association of the HSD3B1 adrenal-permissive homozygous genotype with androgen deprivation therapy resistance in prostate cancer.ObjectiveTo evaluate differences in mortality outcomes by HSD3B1 genetic status among men with prostate cancer.Design, setting, and participantsThis cohort study of patients with prostate cancer who were enrolled in the Million Veteran Program within the Veterans Health Administration (VHA) system between 2011 and 2023 collected genotyping and phenotyping information.ExposureHSD3B1 genotype status was categorized as AA (homozygous adrenal-restrictive), AC (heterozygous adrenal-restrictive), or CC (homozygous adrenal-permissive).Main outcomes and measuresThe primary outcome of this study was prostate cancer-specific mortality (PCSM), defined as the time from diagnosis to death from prostate cancer, censored at the date of last VHA follow-up. Secondary outcomes included incidence of metastases and PCSM in predefined subgroups.ResultsOf the 5287 participants (median [IQR] age, 69 [64-74] years), 402 (7.6%) had the CC genotype, 1970 (37.3%) had the AC genotype, and 2915 (55.1%) had the AA genotype. Overall, the primary cause of death for 91 patients (1.7%) was prostate cancer. Cumulative incidence of PCSM at 5 years after prostate cancer diagnosis was higher among men with the CC genotype (4.0%; 95% CI, 1.7%-6.2%) compared with the AC genotype (2.1%; 95% CI, 1.3%-2.8%) and AA genotype (1.9%; 95% CI, 1.3%-2.4%) (P = .02). In the 619 patients who developed metastatic disease at any time, the cumulative incidence of PCSM at 5 years was higher among patients with the CC genotype (36.0%; 95% CI, 16.7%-50.8%) compared with the AC genotype (17.9%; 95% CI, 10.5%-24.7%) and AA genotype (18.5%; 95% CI, 12.0%-24.6%) (P = .01).Conclusions and relevanceIn this cohort study of US veterans undergoing treatment for prostate cancer at the VHA, the HSD3B1 CC genotype was associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-hydroxysteroid dehydrogenase-1 and the androgen-signaling axis.

Project description:ImportanceThe adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).ObjectiveTo examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data.Design, setting, and participantsThe E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.InterventionsMen were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone.Main outcomes and measuresTwo-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype.ResultsOf 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.Conclusions and relevanceInheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.

Dataset Information

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

Publications

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

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