Researchers Validate Link Between Genetic Variant and Poor Outcomes in Advanced Prostate Cancer

Metastatic prostate cancer patients with an adrenal-permissive variant of the HSD3B1 gene are more likely to have aggressive, early castration-resistant disease and shorter survival, a Cleveland Clinic-led study has found.

The research — the first prospective clinical trial validation of the relationship between HSD3B1 status and clinical outcomes — suggests that genetic testing for the presence of the inherited adrenal-permissive HSD3B1(1245C) allele may help physicians identify patients most likely to benefit from additional, escalated treatment.

Medical oncologist and physician-researcher Nima Sharifi, MD, of Cleveland Clinic’s Lerner Research Institute, Glickman Urological & Kidney Institute and Taussig Cancer Institute, is the study’s senior author.

While androgen deprivation therapy (ADT) to deplete circulating gonadal testosterone is initially effective for treating advanced prostate cancer, tumors eventually are able to overcome medical or surgical castration by synthesizing their own androgens using extragonadal precursor steroids. The recent addition of novel agents such as docetaxel, abiraterone, enzalutamide and apalutamide along with ADT as upfront therapy for advanced prostate cancer has produced a survival benefit, but there are significant outcome variations among patients that indicate tumors’ underlying biologic variability.

The enzyme 3β-hydroxysteroid dehydrogenaseisoenzyme-1 (3βHSD1), encoded by the HSD3B1 gene, catalyzes the first and rate-limiting step in prostate cancer cells’ metabolic conversion of adrenal dehydroepiandrosterone (DHEA) to 5α-dihydrotestosterone (DHT). Dr. Sharifi’s previous research identified the first gain-of-function genetic mutation that increases the conversion of precursor steroids to DHT, permitting tumors to grow in the absence of gonadal testosterone.

The variant adrenal-permissive HSD3B1(1245C) allele encodes for a stable form of the 3βHSD1 enzyme that supports rapid conversion from DHEA to DHT and high levels of DHT in tumor tissue. The stable enzymatic accumulation increases androgen synthesis, enhances androgen receptor activation and accelerates tumor proliferation. In essence, the adrenal-permissive genotype opens the floodgates to DHT, allowing for clinical progression to castration-resistant disease.

The population frequency of the adrenal-permissive variant is disproportionately higher in white men. Retrospective studies by Dr. Sharifi and others involving men with nonmetastatic and metastatic prostate cancer have indicated an association between the adrenal-permissive HSD3B1(1245C) variant and accelerated time to development of castration-resistant disease, reduced metastasis-free survival and reduced overall survival. But these findings have not been validated with prospective studies.

Examining HSD3B1(1245C)’s impact

For the latest study, Dr. Sharifi and colleagues analyzed data from 475 participants already enrolled in a large, multi-center national phase 3 clinical trial (the Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer, or CHAARTED) intended to the assess the efficacy of ADT alone or in combination with docetaxel in prostate cancer.

Dr. Sharifi and his co-investigators compared clinical outcomes between men who carried the adrenal-permissive variant (one or more HSD3B1[1245C] alleles) and those who did not. Eighty-five percent of the CHAARTED trial’s participants were white, as were 90% of the subjects whose DNA was available for genotyping. The analysis conducted by Dr. Sharifi and colleagues focused only on white patients in order to avoid potential confounding genomic factors that could vary by race.

The researchers found that adrenal-permissive HSD3B1(1245C) inheritance is 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. Freedom from castration-resistant prostate cancer at two years post-treatment was significantly lower in patients with low-volume disease and the adrenal-permissive genotype compared to those with the adrenal-restrictive genotype. Overall survival at five years post-treatment also was significantly worse in the adrenal-permissive cohort.

Interestingly, the genetic variant led to shortened survival despite the administration of any other therapies following the development of treatment resistance.

“These findings lay the groundwork for more personalized and effective treatments for prostate cancer,” says Dr. Sharifi. “If men carry this specific testosterone-related genetic abnormality we may be able to individualize their therapy.”

HSD3B1(1245C) was not found to influence clinical outcomes in men with high-volume prostate cancer (defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebrae). Dr. Sharifi notes this is not surprising, since previous studies have shown that disease progression and burden is vastly different between high- and low-volume prostate cancer.

He and his colleagues speculate that the increased genomic alterations present in high-volume disease may make cancer cells less reliant on extragonadally-driven androgen receptor stimulation and may improve access to alternative androgen synthesis pathways, tempering the advantage conferred by the adrenal-permissive allele.

A journey from bench to bedside

Taken together, the study’s findings suggest that the presence of the adrenal-permissive genetic variant can be used to identify men with low-volume metastatic prostate cancer most at risk for quick progression to treatment resistance and earlier death — a discovery with significant implications for clinical care and genetic counseling. A positive germline HSD3B1(1245C) genotyping result could help clinicians determine which patients might benefit from escalated efforts to inhibit the androgen receptor axis in addition to gonadal testosterone suppression.

“These findings represent a seven-year research story that started at the lab bench and has now reached the patient bedside,” says Dr. 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(1245C) variant. This work is another step in that direction.”

A limitation of the study was its lack of diversity due to the restriction of its cohort to white patients to reduce potential confounders. Using a more diverse population to validate the association between HSD3B1(1245C) and adverse clinical will be an important next line of investigation, Dr. Sharifi says.

The research was supported in part by the National Cancer Institute, the U.S. Department of Defense and the Prostate Cancer Foundation. Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and directs the Genitourinary Malignancies Research Center. He has joint appointments in the Taussig Cancer Institute, Glickman Urological & Kidney Institute and Lerner Research Institute. In 2017, he received the national Top Ten Clinical Achievement Award from the Clinical Research Forum for his discoveries linking HSD3B1(1245C) with poor prostate cancer outcomes.