HSD3B1 May Be Associated with Earlier Castration Resistance, Shorter OS in Prostate Cancer

The testosterone-related genetic variant HSD3B1was found to be associated with earlier castration resistance and shorter overall survival (OS) in men with low-volume metastatic prostate cancer, according to a study published in JAMA Oncology. 

Given these findings, HSD3B1may help identify more men who are likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression according to the researchers.¹

“These findings lay the groundwork for more personalized and effective treatments for prostate cancer,” senior author Nima Sharifi, MD, of Cleveland Clinic’s Lerner Research Institute, said in a press release.²“If men carry this specific testosterone-related genetic abnormality we may be able to individualize their therapy.”

Using the phase III E3805 Chemo-hormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED), researchers analyzed 527 available DNA samples and retrospectively determined the HSD3B1germline genotype in 475 white men. The patients were then randomized to castration plus docetaxel (Taxotere) at 75 mg/m²every 3 weeks for 6 cycles or castration alone, and clinical outcomes were evaluated by genotype. 

Of the study cohort, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Freedom from castration-resistant prostate cancer at 2 years was diminished in men with low-volume disease with the adrenal-permissive (51.0% [95% Ci, 40.9%-61.2%]) compared to the adrenal restrictive genotype (70.5% [95% CI, 60%-80.9%]) (P= 0.01). 

At 5 years, OS was worse in men with low volume disease with the adrenal-permissive genotype (57.5% [95% CI, 47.4%-67.7%] vs 70.8% [95% CI, 60.3%-81.3%] [P= 0.03]). Moreover, hazard ratios were 1.89 (95% CI, 1.13-3.14; P= 0.02) for castration-resistant prostate cancer and 1.74 (95% CI, 1.01-3.00; P= 0.045) for death.

There was no association found between genotype and outcomes in men with high-volume disease. Further, there was no interaction between genotype and benefit from docetaxel. 

“These findings represent a 7-year research story that started at the lab bench and has now reached the patient bedside,” said Sharifi. “As the team has shown here, incorporating genetic testing in prostate cancer as part of routine care has significant potential to improve treatment success and quality and length of life for men with prostate cancer who carry the HSD3B1(1235C) variant. This work is another step in that direction.”

Researchers indicated that further studies are warranted to evaluate whether potent androgen receptor antagonists might directly overcome the tumor growth advantage transmitted by the HSD3B1(1245C) allele and yield particular benefit for patients with low-volume disease who have the adrenal permissive genotype. Moreover, a notable limitation of the study is that the analysis was restricted to white men given that white patients accounted for 85% of all of the trial participants.

“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,” the authors wrote. “Accordingly, HSD3B1genotype could be used as a stratification factor for patients with low-volume disease in future clinical trials.”

References:

1. Hearn JWD, Sweeney CJ, Almassi N, et al. HSD3B1Genotype and Clinical Outcomes in Metastatic Castration-Sensitive Prostate Cancer. JAMA Oncology; 2020. doi:10.1001/jamaoncol.2019.6496.

2. Researchers Validate Link Between Genetic Variant and Poor Outcomes in Men with Advanced Prostate Cancer [news release]. Cleveland, Ohio. Published February 13, 2020. newswise.com/articles/researchers-validate-link-between-genetic-variant-and-poor-outcomes-in-men-with-advanced-prostate-cancer?sc=mwhr&xy=10021790. Accessed March 4, 2020.