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

Abstract

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.

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).…”

Association of Missense Polymorphism inHSD3B1With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone

“…Previous studies investigating the effect of HSD3B1 on oncological outcome have demonstrated higher risk of progression and all-cause mortality in men carrying the variant allele. 11 , 12 , 13 Although ethnic distribution in the study by Agarwal et al 12 is not presented, the study by Hearn et al 11 included mainly white men. In contrast to these US reports, the Chinese study by Wu et al 22 showed significant risk of CRPC in men carrying variant allele but failed to show significant differences in PFS and OS.…”

“…Recent studies have demonstrated that genetic polymorphism in HSD3B1 is associated with oncological outcome among residents in the United States treated with ADT, where men carrying variant alleles showed worse prognosis. 11 , 12 , 13 Thus, genetic variation in HSD3B1 (1245C) genotype is a promising predictive biomarker of positive ADT response among men with prostate cancer. However, its impact on prognosis among people of different ethnicities remains unclear, where the frequency of the variant allele would differ among ethnicities.…”

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

“…Although 3-keto-5α-Abi is a modest AR agonist that is substantially weaker than DHT, its presence in the near-complete absence of endogenous androgens in the setting of gonadal and extragonadal androgen deprivation may be deleterious. Furthermore, clinical outcomes data consistently show that HSD3B1(1245C) inheritance confers a switch to a decreased tumor dependence on gonadal androgens and increased dependence on extragonadal androgens (8)(9)(10)(11)(12), together suggesting that this genetically defined population that identifies a certain steroid physiology may have a disproportionate benefit from CYP17A1 blockade with a nonsteroidal CYP17A1 inhibitor (12). In contrast to nonsteroidal CYP17A1 inhibition, HSD3B1(1245C) inheritance does not appear to correlate with duration of response to AA therapy (24).…”

“…The common (20%-35% allele frequency) germline variant HSD3B1(1245C) encodes for a protein degradation-resistant 3βHSD1, which effectively increases intratumoral testosterone and/ or DHT synthesis from extragonadal precursor steroids (7). Patients with advanced prostate cancer who inherit the HSD3B1(1245C) variant have worse outcomes after initiation of ADT and more rapid development of CRPC because they have enabled enzymatic machinery that makes use of extragonadal precursor steroids (8)(9)(10)(11). On the other hand, HSD3B1(1245C) inheritance may result in a tumor dependence on extragonadal precursors, as evidenced by its association with more sustainable clinical responses to the nonsteroidal CYP17A1 inhibitor, ketoconazole (12).…”