HSD3B1 gene variant predicts ADT resistance
medwireNews: An inherited variant of HSD3B1 is a “powerful” biomarker of resistance to androgen deprivation therapy (ADT) in men with castration-resistance prostate cancer, say US researchers.
They propose that the presence of one or more copies of the 1245A>C germline polymorphism could “be used to identify men who might benefit a priori from escalated therapy”.
The primary cohort included 118 patients treated with ADT for post-prostatectomy biochemical recurrence at the Cleveland Clinic in Ohio, USA. Genotyping of non-neoplastic tissue isolated from prostatectomy specimens showed that 37% were homozygous for the wild-type HSD3B1 allele, while 53% and 10% had one and two copies of the variant allele, respectively.
The HSD3B1 genotype correlated significantly with progression-free survival (PFS), which decreased in a stepwise fashion depending on the number of variant alleles. Specifically, median PFS was 6.6 years for homozygous wild-type patients, 4.1 years for those heterozygous for the variant allele and 2.5 years for men who were homozygous for the variant allele.
And carrying one or two versus no copies of the variant HSD3B1 allele was significantly associated with a respective 1.7- and 2.4-fold increased risk of progression, which in this study encompassed the first occurrence of an increase in prostate-specific antigen levels during ADT, radiographic or clinical progression, or initiation of second-line treatment.
The association between HSD3B1 genotype and PFS was also observed in two validation cohorts from the Mayo Clinic (Rochester, Minnesota, USA) comprising 137 patients who received ADT after post-prostatectomy biochemical or nonmetastatic failure and 188 men with metastatic disease.
In the primary study cohort, inheritance of at least one copy of the variant HSD3B1 allele was also linked to significantly worse distant metastasis-free survival and overall survival, with a similar stepwise decrease in survival times with the number of variant alleles.
The findings are “biologically credible”, say Nima Sharifi, from the Cleveland Clinic, and co-investigators, explaining that the HSD3B1 1245A>C variant encodes an altered version of the 3β-hydroxysteroid dehydrogenase-1 enzyme that is known “to increase intratumoural conversion of androgen precursor steroids to more potent androgens that can drive disease progression, despite castration”.
If validated in prospective studies, they believe that “[t]he ramifications of a biomarker able to predict ADT resistance are far-reaching.” These include not only identifying patients most likely to benefit from ADT itself, but also potentially helping to make decisions regarding chemohormonal therapy and active surveillance.
Writing in a related commentary in The Lancet Oncology, Emmanuel Antonarakis (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA) notes that the early use of ADT plus abiraterone in men with a variant allele is “especially intriguing”.
Abiraterone, which reduces extra-gonadal androgen synthesis, might have greater efficacy in individuals heterozygous or homozygous for the 1245A>C allele, “whose tumours might be especially dependent on extra-gonadal androgens”, he speculates.
Highlighting the need for future research to evaluate this hypothesis, Antonarakis concludes: “If these biomarker studies bear fruit, they might show that an inherited genetic vulnerability in one setting (gonadal suppression) could be converted into a therapeutic opportunity in another (addition of abiraterone).”
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