Genetic Variant Linked to Poor Advanced Prostate Cancer Outcomes

A testosterone-related genetic variant (HSD3B2[1245C]) is linked to poor outcomes in advanced prostate cancer according to a recent study published in JAMA Oncology.

In particular, HSD3B1(1245C) is associated with more aggressive metastatic prostate cancer and shorter survival rates in men with the disease. Researchers hope the results of this clinical trial, the first of its kind validating the relationship of the variant to clinical outcomes, will help physicians identify patients who may benefit from additional and more aggressive treatment, according to a press release.

HSD3B1(1245C) is an adrenal-permissive allele that augments extragonadal dihydrotestosterone synthesis and is found with the highest frequency in white men. Researchers collected data from men enrolled in the E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED), a multi-center phase 3 trial. Specifically, the trial included men who underwent castration with or without docetaxel treatment after being newly diagnosed metastatic prostate cancer.

Researchers found 527 patients in the study had available DNA samples. They retrospectively determined 475 white men had the HSD3B1 germline genotype and analyzed the cohort’s clinical outcomes by genotype. The study also measured 2-year freedom from castration-resistant prostate cancer (CRCP) and 5-year overall survival rates. Of the 475 men with the germline genotype, 270 (56.8%) inherited HSD3B1 (1245C).

The inheritance of HSD3B1(1245C) was found to be “associated with faster progression to treatment resistance and shorter overall survival in men with low-volume metastatic prostate cancer regardless of the use of docetaxel.” In addition, researchers discovered “the genetic variant led to shortened survival despite the administration of any other therapies following the development of treatment resistance.”

According to authors, at 2 years, freedom from CRCP was diminished in men with low-volume disease with HSD3B1(1245C), at 51%, compared to the adrenal-restrictive genotype (HSD3B1[1245A]) subgroup, at 70.5% (95% CI; P = .01). After 5 years, overall survival was also worse in men with low-volume disease and HSD3B1(1245C), compared to the adrenal-restrictive group (57.5% [95% CI] vs 70.8% [95% CI; P = .03]).

“These findings lay the groundwork for more personalized and effective treatments for prostate cancer,” said Nima Sharifi, MD, a lead author of the study. “If men carry this specific testosterone-related genetic abnormality we may be able to individualize their therapy."

The presence of HSD3B1(1245C) did not influence clinical outcomes in men with high-volume prostate cancer, the report found. Due to the lack of diversity of men included in CHAARTED, the results may not be generalized to a more diverse population. HSD3B1(1245C) was found in 7 of 52 nonwhite men (13.5%; P < .001) in the study.

However, authors note, “by focusing the analysis on white patients, we sought to reduce potential cofounders that might mask the effect of the HSD3B1 genotype.”

Reference

Hearn JWD, Sweeney CJ, Almassi N, et al. HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer [published online February 13, 2020]. JAMA Oncol. doi:10.1001/jamaoncol.2019.6496.