Genotype linked to shorter survival in metastatic prostate cancer

Inheriting the adrenal-permissive HSD3B1(1245C) genotype is associated with worse outcomes in low-volume metastatic prostate cancer and might someday help identify patients who could benefit from escalated therapy, according to a recent study.

In essence, some patients are genetically predisposed to having their prostate cancers make their own potent androgens, such as testosterone or dihydrotestosterone (DHT), from non-testicular sources, according to study author Nima Sharifi, MD, of Cleveland Clinic Genitourinary Malignancies Research Center, Cleveland.

“This comes from germline inheritance of an effectively ‘fast’ enzyme by the gene HSD3B1 that allows for prostate cancer to make these androgens. What this means clinically is that men with low-volume metastatic prostate cancer who inherit this fast form of HSD3B1 treated with medical or surgical castration progress more quickly and have shorter survival compared with men who do not inherit this fast enzyme,” Dr. Sharifi said.

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Development of castration-resistant prostate cancer is driven in large part to the tumor’s capability of converting nongonadal or extragonadal precursor steroids. While the adrenal-permissive HSD3B1 (1245C) allele augments extragonadal DHT synthesis, the adrenal-restrictive allele limits extragonadal DHT synthesis, according to Dr. Sharifi.

The adrenal permissive allele is common, occurring with about 35% frequency in Caucasians, meaning one in two men will harbor at least one allele copy. It is most common in people of European descent and tends to be less common in people of African and East Asian descent, Dr. Sharifi said.

The study, published in JAMA Oncology (Feb. 13, 2020 [Epub ahead of print]), looks at germline data from 475 Caucasian men in the Chemo-hormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) clinical trial. CHAARTED was a phase III study in which researchers randomized men with metastatic castration-sensitive prostate cancer to castration versus castration plus docetaxel (Taxotere).

“Our current study is a validation in a phase III clinical trial of men who received castration versus castration plus docetaxel chemotherapy. It is the first clinical trial level validation and builds upon our initial discovery in the laboratory and several retrospective clinical studies that determined poor clinical outcomes in men with adrenal-permissive HSD3B1 genetics,” Dr. Sharifi said.

Dr. Sharifi and colleagues found that freedom from castration-resistant prostate cancer at 2 years for men with low-volume disease was 51% for the adrenal-permissive genotype versus 70.5% in men with low-volume disease and the adrenal-restrictive genotype.

Continue to the next page for moreOverall survival at 5 years among low-volume disease patients with the adrenal-permissive genotype was 57.5% compared to 70.8% in those with low-volume disease and the adrenal-restrictive genotype.

There was no association between the HSD3B1 allele and clinical outcomes in men who had high-volume castration-sensitive prostate cancer. Dr. Sharifi said he suspects that’s because high-volume prostate cancer might be more genomically and epigenetically complex.

The authors also did not find an association between pathology and the presence or absence of the allele.

The phenotype conferred by the adrenal permissive allele appears to be specific to castration-resistant prostate cancer and the absence of gonadal testosterone, according to Dr. Sharifi.

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Dr. Sharifi, who in 2017 received the national Top Ten Clinical Achievement Award from the Clinical Research Forum for his discoveries linking HSD3B1(1245C) with poor prostate cancer outcomes, said the newest findings are on the heels of 7 years of research, which started at the lab bench.

“Right now, we do not use genetic information to determine the systemic treatment, such as hormonal therapy or combination therapy, for patients with newly diagnosed metastatic prostate cancer. These findings may one day be used to help determine the right treatment for patients given their own genetic characteristics,” he said.

But more research is needed before changing the medical management of metastatic prostate cancer patients, he said.

Dr. Sharifi receives personal fees from Janssen and Pfizer but not for this study. He holds a patent on the HSD3B1.