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

Abstract

Summary Background HSD3B1(1245A>C) has been mechanistically linked to castration-resistant prostate cancer by encoding an altered enzyme that augments dihydrotestosterone synthesis. We hypothesized that men inheriting the HSD3B1(1245C) allele would exhibit resistance to androgen deprivation therapy (ADT). Methods We determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. Patients who received postoperative adjuvant or salvage radiotherapy were eligible, provided they had residual active disease as reflected by continued increase in their PSA after treatment. We analyzed progression-free survival (PFS; primary endpoint), distant metastasis-free survival (DMFS), and overall survival (OS) according to HSD3B1 genotype. Multivariable analyses were performed to assess the independent predictive value of HSD3B1 genotype on outcomes. Results were externally validated in two additional cohorts, including a second post-prostatectomy biochemical failure cohort as well as a metastatic cohort. There was no age limit for eligibility in the primary or validation cohorts. Findings The study included 443 patients: 118 in the primary cohort, 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median PFS diminished as a function of the number of variant alleles inherited: 6.6 years in homozygous wild-type men (95% CI, 3.8 to not reached); 4.1 years in heterozygotes (95% CI, 3.0 to 5.5); and 2.5 years in homozygous variant men (95% CI, 0.7 to not reached); P=0.011. Median DMFS likewise decreased according to the number of variant alleles inherited: 9.1 years (95% CI, 7.4 to not reached); 6.8 years (95% CI, 4.3 to 7.4); and 3.6 years (95% CI, 1.0 to 7.3), respectively; P=0.014. Finally, OS diminished with the number of variant alleles inherited: 5-year and 10-year OS 82% (95% CI, 69 to 94) and 55% (95% CI, 35 to 75) in homozygous wild-type men; 74% (95% CI, 62 to 85) and 35% (95% CI, 21 to 49) in heterozygotes; and 58% (95% CI, 30 to 86) and 0% in homozygous variant men; P=0.0064. On multivariable analysis, the hazard ratio (HR) for progression was 1.6 for men with at least one variant allele (95% CI, 1.0 to 2.7; P=0.074), which compared favorably with Gleason score (HR 1.3 for Gleason score 8–10 vs. 6–7; 95% CI 0.8 to 2.0; P=0.31), though neither factor reached statistical significance with the small sample size. The impact of homozygous variant genotype on metastasis (HR 2.8; 95% CI, 1.1 to 6.7; P=0.025) and death (HR 3.5; 95% CI 1.3 to 9.5; P=0.013) was maintained on multivariable analysis. Findings in the external cohorts independently validated the impact of HSD3B1(1245C) on outcomes. Interpretation Inheritance of the HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. Our findings nominate HSD3B1 as a powerful genetic biomarker capable of distinguishing men who are a priori ...

Direct Metabolic Interrogation of Dihydrotestosterone Biosynthesis from Adrenal Precursors in Primary Prostatectomy Tissues

“…Thus, this shift towards AD as the more favorable substrate may represent a critical metabolic switch in CRPC that heralds a compensatory increase in adrenal steroid utilization for DHT biosynthesis. This is supported by other independent observations illustrating the impact of enhanced adrenal steroid metabolism in CRPC—for instance the clinical consequence of a gain-of-function missense variant in 3β-HSD isoenzyme-1, which dramatically increases the rate of DHEA→AD conversion (13,31,32). Remarkably, this metabolic switch towards AD also appears to coincide with a conspicuous loss in the relative ability of 5α-reductase to harness T. In fact, the majority of prostate cancer cell lines and sampled patient metastases demonstrate very low capacity to convert T→DHT and thus exhibit an idiosyncratic dependence on adrenal precursor steroids (11).…”

Lipid quantification by Raman microspectroscopy as a potential biomarker in prostate cancer

“…PCa is primarily a hormone-driven cancer and need androgens to grow, which is why androgen deprivation therapy (castration and administration of anti-androgens) or ADT is mostly employed by clinicians to manage this cancer [41]. Unfortunately, PCa re-emerges with time (termed as CRPC), which is more aggressive and resistant against current therapeutics, and reactivation of AR signaling promotes the return of PCa [42–45]. Sustained activation of AR signaling following ADT has been attributed to de novo steroidogenesis by PCa cells [46–49].…”

Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities

“…However, 3βHSD1 activity is low in LAPC4 cells, and therefore this comparison likely was more selectively focused on Gal and abiraterone. Consequences of downstream Gal metabolites are more likely to be seen in models, tumors and patients that have the 3βHSD1 N367T missense that accumulates and results in high activity(Hearn et al, 2016). …”