Last Updated on
February 28, 2020 – A very recent report elucidates the possible prospective power of the knowledge about the genetic background of patients when concerned with certain clinical endpoints (disease states) and associated genes.
The researchers in the present study analyzed outcomes in white men enrolled in the E3805 CHAARTED clinical trial according to HSD3B1 genotype, hypothesizing that accentuated extragonadal dihydrotestosterone (DHT) synthesis associated with the adrenal-permissive allele would be associated with more rapid development of castration-resistant prostate cancer (CRPC) and lower overall survival.
The HSD3B1(1245C) adrenal-permissive allele encodes a stable enzyme that allows for more robust conversion from dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT), whereas the adrenal-restrictive HSD3B1(1245A) allele encodes a more rapidly degraded enzyme that limits conversion from DHEA to DHT. Retrospective studies have linked inheritance of the adrenal-permissive allele to worse clinical endpoints (i.e., prostate cancer outcomes).
Thus, among the 475 white men included in the study, 56.8% had the adrenal-permissive genotype, versus only 13.5% of nonwhite men. Most men (n=301) had high-volume disease, and 174 had low-volume disease. Freedom from CRPC at two years was significantly lower in men with low-volume disease with the adrenal-permissive genotype (51.0%) versus the adrenal-restrictive genotype (70.5%), the researchers found. In multivariable analysis, the adrenal-permissive genotype was associated with a 89% higher risk of CRPC. In contrast, there was no significant difference based on HSD3B1 genotype in freedom from CRPC at two years in men with high-volume disease.
Overall, the adrenal-permissive HSD3B1 genotype is associated with worse clinical outcomes in men with metastatic castration-sensitive prostate cancer. Carrying one (heterozygous individuals) or two (homozygous individuals) copies of the allele is associated with a shorter interval from androgen-deprivation therapy to castration-resistant prostate cancer, as well as shorter overall survival, in men with low-volume metastatic prostate cancer, Survival at five years was significantly worse in men with low-volume disease who had the adrenal-permissive genotype (57.5%) than in those with the adrenal-restrictive genotype (70.8%).
Men with low-volume disease did not benefit significantly from docetaxel, but men with high-volume disease did benefit, regardless of HSD3B1 genotype. Broadly, HSD3B1 genotyping tells us how much an individual man’s tumor is dependent on extragonadal (or adrenal) androgens. Additional studies will will eventually help us understand how best to use this underlying genetic information for clinical management of prostate cancer.
See here a short sequence on prostate cancer and treatment options: