Researchers Identify Genetic Mutation Associated With Poor Outcomes in Prostate Cancer

Investigators think they may have found a strong predictor of which men with prostate cancer will develop resistance to androgen deprivation therapy (ADT). They are reporting in The Lancet Oncology that inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis appears to be associated with prostate cancer resistance to ADT.

The investigators theorize that HSD3B1 could potentially be a powerful genetic biomarker capable of distinguishing which men may need less aggressive therapy from those whose warrant early escalated therapy. A team of researchers from the Cleveland Clinic and the Mayo Clinic have been studying this issue for some time and now hope these new findings will lead to a simple blood test to detect the presence of the polymorphism, personalizing prostate cancer treatment.

“A simple blood test could allow us to personalize therapy by telling us which patients need to be treated more aggressively, such as with more intensive hormonal therapy,” said study investigator Nima Sharifi, MD, who is on the medical staff in Cleveland Clinic’s Lerner Research Institute Department of Cancer Biology, Glickman Urological & Kidney Institute, and Taussig Cancer Institute, in a news release. “On the contrary, patients with metastatic cancer who do not carry the polymorphism may fare better with ADT alone.”

In 2013, Dr. Sharifi discovered that this resistance is caused by a single nucleotide polymorphism (SNP) in the HSD3B1 gene, which encodes an enzyme that is crucial to the androgen synthesis process. The altered enzyme enables prostate cancer cells to generate more of their own androgens when treated with ADT, enhancing the cancer’s ability to spread.

For this particular study, Dr. Sharifi and colleagues sequenced the HSD3B1 gene in 443 men in three different cohorts who underwent ADT: 118 in the primary cohort who underwent prostatectomy, 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. They found a strong correlation between the presence of the SNP HSD3B1 (1245C) and poorer survival (progression-free, distant metastasis-free, and overall survival). In addition, they found that patients who had inherited two copies of the gene with the polymorphism (homozygotes) fared much worse than those who had only inherited one allele (heterozygotes). 

Relative to the homozygous wild-type genotype, inheritance of two copies of the variant allele was predictive of decreased progression-free survival. The same was true for inheritance of one copy of the variant allele. The investigators reported similar findings for distant metastasis-free survival and overall survival.

The authors write that this identification might have ramifications for selective early incorporation of highly-potent inhibitors of the androgen receptor axis. In addition, they report that this could potentially identify certain patients for chemohormonal therapy. Investigators at the Cleveland Clinic are now conducting a phase 1 clinical trial testing alternative treatments for prostate cancer patients who have inherited HSD3B1 (1245C).