Germline genetics and different responses to different types of ADT

Three articles in the October 12 issue of JAMA Oncology address the fact that a very specific germline mutation to the so-called HSD3B1 gene affects response to standard forms of initial androgen deprivation therapy and related factors. These are the three articles:

Much of the research presented is summarized in a report on the ScienceDaily web site that is probably som ewhat easier to read and is based on a media release from the Cleveland Clinic.

Basically, the studies reported deal with work carried out by two different research teams, both under the leadership of Nima Sharifi of the Cleveland Clinic. Fundamentally,. what they have shown is that patients with a mutated form of the HSD3B1 gene called HSD3B1 (1245A>C) produce a slightly different form (an allele) of the enzyme called 3β-hydroxysteroid dehydrogenase-1 or 3βHSD1.

3βHSD1 is an important enzyme because it is the catalyst (the biochemical facilitator) of the transformation of adrenal antiandrogens into dihydrotestosterone (the most potent antiandrogen that is critical to the growth of prostate cancer cells). Standard ADT works very well in shutting down the activity of the normal form of 3βHSD1. But standard ADT doesn’t work anything like as well on the mutant allele of 3βHSD1, and so patients with this mutant form of 3βHSD1 don’t get the same degree of benefit from standard ADT as the rest of us.

What Sharifi and his colleagues have been able to do is:

  • To show, in the study by Hearm et al., that in men with post-radiation therapy biochemically recurrent prostate cancer who are started on standard ADT, the presence of the variant allele of 3βHSD1 — based on the presence of the inherited, mutant HSD3B1 (1245A>C) gene — was predictive of a shorter time to metastasis (TTM) from initiation of ADT but not predictive of any change in progression-free survival (PFS) or overall survival (OS).
  • To show, in the study by Almassi et al., that when men with castration-resistant prostate cancer (CRPC) are treated with a non-steroidal CYP17A1 inhibitor (ketoconazole in this study) the patients’ median PFS improved in a dose-dependent manner with increasing frequency of the presence of the inherited, mutant HSD3B1 (1245A>C) gene: 5.4 months for 0 alleles; 9.7 months for 1 allele; 15.2 months for 2 alleles.

So what we basically seem to have here is a potential germline genetic test for what initial form of ADT (standard ADT or ADT that starts with the use of a CYP17A1 inhibitor) should be given first for men starting on ADT after post-radiation therapy progression.

The next step will need to be whether patients with the inherited, mutant HSD3B1 (1245A>C) gene respond better to abiraterone acetate or to enzalutamide than to ketoconazole, but we do seem to be well on the way to better defining the patients most in early need for treatment with the newer, so-called “second-line” antiandrogens.

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