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Testosterone-Related Genetic Mutation Associated With Poorer Survival in Prostate Cancer


A collaborative Cleveland Clinic–Mayo Clinic team of researchers has shown for the first time that patients with advanced prostate cancer are more likely to die earlier of their disease if they carry a specific testosterone-related genetic abnormality. The findings, published by Hearn et al in The Lancet Oncology,1 suggest that a specific, inherited polymorphism, or inherited genetic change, in the HSD3B1 gene renders standard therapy for metastatic prostate cancer less effective. The researchers anticipate that these findings will lead to a simple blood test to detect the presence of the polymorphism, personalizing cancer treatment and indicating which patients may need more aggressive treatment.

Nima Sharifi, MD

Nima Sharifi, MD

The team, led by Cleveland Clinic’s Nima Sharifi, MD, studied three groups of men at the Cleveland Clinic and the Mayo Clinic who were treated with androgen-deprivation therapy, the standard of care for treatment of metastatic prostate cancer. Although the treatment is widely successful for many patients, eventually prostate tumors are able to circumvent androgen-deprivation therapy, and patients become resistant to the treatment because the tumors make their own ­androgens.

In 2013, Dr. Sharifi discovered this resistance is caused by a single-nucleotide polymorphism 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 androgen-deprivation therapy, enhancing the cancer’s ability to flourish and spread.

Study Findings

In the current study, Dr. Sharifi and colleagues sequenced the HSD3B1 gene in 443 men in 3 different cohorts who had undergone androgen-deprivation therapy and recorded their outcomes. They found a strong correlation between the presence of the single-nucleotide polymorphism 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), suggesting the extra copy of the polymorphism may lead to increased rogue-androgen synthesis.

These results confirm the researchers’ previous mechanistic findings about HSD3B1 (1245C) and suggest that the polymorphism is a strong predictor of which patients will develop resistance to androgen-deprivation therapy. “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 Dr. Sharifi. “On the contrary, patients with metastatic cancer who do not carry the polymorphism may fare better with androgen-deprivation therapy alone.” ■

Disclosure: For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Hearn JW, AbuAli G, Reichard CA, et al: HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: A retrospective, multicohort study. Lancet Oncol. August 26, 2016 (early release online).



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