Genetic link to poorer outcomes in men with low-volume metastatic CSPC
medwireNews: Prospective data now confirm that White men with low-volume metastatic castration-sensitive prostate cancer (CSPC) who have the adrenal-permissive HSD3B1 genotype have poorer outcomes than those with the adrenal-restrictive genotype.
Researcher Nima Sharifi (Cleveland Clinic, Ohio, USA) and colleagues explain in JAMA Oncology that retrospective analyses of at least seven cohorts of men with nonmetastatic or metastatic disease have suggested that “inheritance of the adrenal-permissive HSD3B1(1245C) allele is associated with decrements in meaningful clinical end points,” such as time to castration-resistant prostate cancer (CRPC) and overall survival (OS), but prospectively collected evidence was lacking.
Therefore, the team obtained DNA samples from 475 White men – a population with a “disproportionately high” frequency of the adrenal-permissive HSD3B1 allele – with newly diagnosed metastatic CSPC participating in the phase 3 E3805 CHAARTED trial of androgen deprivation therapy (ADT) with or without docetaxel, and analyzed clinical outcomes by genotype separately for men with low- and high-volume disease.
Overall, 56.8% of participants were found to have the adrenal-permissive genotype, with similar proportions among those with low- and high-volume disease.
In the 174 men with low-volume disease, a significantly smaller proportion of those with the adrenal-permissive allele were free from CRPC at 2 years than their counterparts with the adrenal-restrictive allele, at 51.0% versus 70.5%. The difference remained significant after adjustment for known prognostic factors, with a hazard ratio (HR) of 1.89.
Low-volume disease patients with the adrenal-permissive genotype also had a significantly worse 5-year OS rate, at 57.5% compared with 70.8% for those with the adrenal-restrictive genotype. Again, the poorer outcomes remained after adjustment for known prognostic factors, with an HR for death of 1.74.
There was no such association between the HSD3B1 genotype and outcomes among the 301 men with high-volume disease, and there was also “no interaction between genotype and benefit from docetaxel,” say Sharifi et al.
Specifically, men with high-volume disease had better outcomes with the addition of docetaxel to ADT irrespective of genotype, “whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” they write.
The researchers conclude: “This information could assist clinicians in counseling patients and guide researchers in identifying those for whom escalated androgen receptor axis inhibition beyond mere gonadal testosterone suppression is most warranted.
“Accordingly, HSD3B1 genotype could be used as a stratification factor for patients with low-volume disease in future clinical trials.”
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