The risk of dying of prostate cancer doubled in the presence of a genetic mutation affecting testosterone production, a large prospective cohort study showed.

The 5-year risk of prostate cancer-specific mortality (PCSM) increased from 1.7% to as much as 4%, depending on the genotype of the HSD3B1(1245C) allele. In a subgroup of patients with metastatic prostate cancer, the genotype-specific 5-year PCSM increased from 17.9% to 36%. Multivariable analysis confirmed a significant association between HSD3B1 genotype and PCSM.

Use of HSD3B1 as a biomarker could help identify patients who might benefit from treatment targeting the enzyme involved in extragonadal testosterone production, reported Julie A. Lynch, PhD, of the Veterans Affairs Salt Lake City Health Care System in Utah, and co-authors in JAMA Network Open.

“Our findings suggest the HSD3B1 CC genotype is associated with inferior PCSM among all patients and in individuals who develop metastatic disease,” the authors wrote. “Additionally, we found that the HSD3B1 CC genotype is less common in Black men than in white men. To our knowledge, this is the largest study to date investigating the prognostic significance of HSD3B1 genotype status in prostate cancer within a racially heterogeneous patient population.”

“Consistent with other analyses from the VA healthcare system (where access to care is more consistent), Black race was not associated with worse outcomes in our study,” they added. “Future research in tracking PSA [prostate-specific antigen] before and after ADT [androgen deprivation therapy] to assess response based on HSD3B1 genotype are needed.”

The study represents “a major leap forward” in understanding the biochemical mechanisms and cancer-related outcomes for the adrenal-permissive HSD3B1 allele, according to the authors of an accompanying commentary.

“Despite the associations with prostate cancer mortality, homozygous adrenal-permissive inheritance was not associated with prostate cancer Gleason category, prostate-specific antigen at diagnosis, or the incidence of metastases,” wrote Lina Schiffer, PhD, and Nima Sharifi, MD, of the University of Miami Miller School of Medicine in Florida. “Together, these data are in line with HSD3B1 acting outside the realm of traditional oncogenic pathways … and instead specifically revealing its effects after the initiation of hormonal therapy and hastening the development of hormone therapy resistance and lethality.”

Describing HSD3B1 as “an invisible stimulator of prostate cancer mortality,” Schiffer and Sharifi said germline-panel assessment of nonmetastatic prostate cancer should include HSD3B1.

“Detection of homozygosity can impact disease management because it identifies men with more lethal prostate cancer that is not otherwise captured by current clinical prognostic factors and provides an opportunity to treat at the time of localized disease prior to tumor dissemination and need for hormonal therapy,” they added.

ADT has a long history as frontline treatment for prostate cancer. Most patients initially respond to ADT, but a subset develop castration-resistant prostate cancer (CRPC) with a poor prognosis, Lynch and co-authors noted in their introduction. Multiple androgen-dependent mechanisms of ADT resistance have been identified, including de novo androgen synthesis from cholesterol by 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1).

Encoded by HSD3B1, 3β-HSD1 catalyzes the rate-limiting step of dehydroepiandrosterone conversion that results in a non-testicular source of testosterone and 5α-dihydrotestosterone, the authors explained. HSD3B1 has a single nucleotide variant whereby two different germline missense-encoding alleles result in distinct activities of the 3β-HSD1 protein: HSD3B1(1245A) and HSD3B1(1245C).

An accumulation of evidence has shown an association between HSD3B1 inheritance and prostate cancer outcomes. HSD3B1(1245A) is associated with worse outcomes in patients after prostatectomy and radiotherapy and in the setting of metastatic hormone-sensitive prostate cancer and CRPC. HSD3B1(1245C) is associated with resistance to ADT, androgen receptor signaling agents, and CYP17A1 inhibition. Outcomes are more closely associated with homozygosity for HSD3B1(1245C) [CC genotype] and more variable with the AC genotype.

Lynch and colleagues evaluated differences in outcomes for prostate cancer on the basis of HSD3B1 genetic status, testing the hypothesis that homozygosity for HSD3B1(1245C) would be associated with worse outcomes.

Data for the analysis came from patients enrolled from 2011 to 2023 in the ethnically diverse Million Veteran Program (MVP) of the Veterans Health Administration. The investigators included 5,287 participants who developed prostate cancer after enrollment in the MVP and complete clinical and HSD3B1 genotyping data.

Participants were categorized by HSD3B1 genotype: AA (homozygous adrenal-restrictive), AC (heterozygous adrenal-restrictive), and CC (homozygous adrenal-permissive). The primary outcome was PCSM, and secondary outcomes included incidence of metastatic disease and PCSM in predefined subgroups.

The results showed that 402 patients (7.6%) had the CC genotype, 1,970 (37.3%) had the AC genotype, and 2,915 (55.1%) had the AA genotype. The 5-year PCSM rate by genotype was:

• CC: 4%
• AC: 2.1%
• AA: 1.9%

Prostate cancer mortality was significantly higher in men with the CC genotype versus the other two (P=0.02). Lynch and team also determined PCSM at 5 years for 619 patients who developed metastatic disease at any time. The cumulative incidence of PCSM at 5 years in patients with the CC genotype was 36%, which was significantly higher (P=0.01) than that for the AA genotype (18.5%) and the AC genotype (17.9%).

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