HSD3B1 Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer

Abstract

The 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).OBJECTIVE To 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.INTERVENTIONS Men were randomized to castration plus docetaxel, 75 mg/m 2 , every 3 weeks for 6 cycles or castration alone.MAIN OUTCOMES AND MEASURES Two-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 (Ն1 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 RELEVANCE Inheritance 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.

Examining HSD3B1 as a possible biomarker to detect prostate cancer patients who are likely to progress on ADT

“…Hearn et al have demonstrated this in their recent results using a population derived from the CHAARTED trial, and previous studies have alluded to this. 5 Current data support the idea of HSD3B1 as a predictive biomarker of progression on ADT therapy. The downside of this possible biomarker is that it is not applicable to all races.…”

“…4 Retrospective studies have suggested that the inheritance of the variant allele, HSD3B1(1245 C), is linked to decreased progression-free survival (PFS) and overall survival (OS) when compared to individuals with the wild-type allele, HSD3B1(1245A). 5 The Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) examined the clinical benefit of castration with or without docetaxel in men with metastatic prostate cancer. A 2020 study published in JAMA Oncology determined the HSD3B1 germline genotype in 475 white men who participated in the CHAARTED trial to explore clinical outcomes in relation to the determined genotype.…”

“…A 2020 study published in JAMA Oncology determined the HSD3B1 germline genotype in 475 white men who participated in the CHAARTED trial to explore clinical outcomes in relation to the determined genotype. 5 If a patient had no HSD3B1(1245 C) alleles, they were defined as adrenal restrictive. Adrenal permissive was defined as one or more HSD3B1(1245 C) alleles.…”

“…The allele itself presents much higher in white men; therefore, its role as a biomarker is currently limited to that population. 5 More studies in other races need to be conducted to determine if this trend extends past white males.…”

HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

“…The HSD3B1(1245A) allele encodes for an adrenal restrictive enzyme that limits conversion from DHEA to downstream androgens, whereas the HSD3B1(1245C) allele encodes for an adrenal permissive enzyme that results in increased metabolic flux from DHEA to more potent androgens (16). Multiple studies from the United States, Japan, and Spain, now further confirmed in a phase 3 clinical trial, clearly show that men with advanced prostate cancer treated with castration who inherit the adrenal permissive 3β-HSD1 enzyme, which confers more rapid conversion from DHEA to potent androgens, have more rapid onset of androgendriven disease progression (17)(18)(19)(20)(21)(22). These studies establish that clear clinical phenotypes are associated with HSD3B1 genotypes that biochemically confer fast and slow metabolic flux to potent androgens.…”