From the Journals

Adrenal-permissive genotype linked to poor prognosis in prostate cancer



Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.

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