Genetic Variation Linked to Poorer Outcomes After Radiation and ADT in Veterans With Prostate Cancer

An analysis of the Million Veterans Program (MVP) suggests that a genetic variant in the HSD3B1 gene may contribute to worse outcomes for veterans undergoing curative therapy for prostate cancer. The study, which evaluated men treated with definitive radiation therapy and androgen deprivation therapy (ADT), found that those with the adrenal-permissive HSD3B1(1245C) genotype experienced higher rates of recurrence and disease progression compared to other genotypes.

The investigation drew on the extensive Veterans Health Administration (VHA) database through the Veterans Informatics and Computing Infrastructure (VINCI). Researchers identified 3170 men diagnosed with localized prostate cancer after enrolling in the MVP who subsequently received both radiation therapy and ADT. The HSD3B1 gene, which influences androgen synthesis, was categorized into 3 genotypes: homozygous adrenal-restrictive (AA), heterozygous adrenal-restrictive (AC), and homozygous adrenal-permissive (CC).

Patients were tracked for 3 major outcomes: biochemical recurrence (BCR), progression to metastatic castration-resistant prostate cancer (mCRPC), and cancer-specific mortality (CSM). Mortality data were obtained through the National Death Index, with follow-up censored as of December 31, 2021. Multivariable Cox proportional hazard models adjusted for cancer stage, treatment factors, and demographics were applied to assess associations between genotype and clinical outcomes.

Among participants, 6.6% carried the CC genotype, 34.9% had the AC genotype, and 58.5% had the AA genotype. Compared to men with the adrenal-restrictive (AA or AC) genotypes, those with the adrenal-permissive CC variant had significantly higher risks of biochemical recurrence and progression to MCRPC.

Specifically, the CC group demonstrated nearly double the risk of biochemical recurrence (hazard ratio [HR], 1.91; 95% CI, 1.27-2.86; P = .0018) and an 84% higher risk of developing mCRPC (HR, 1.84; 95% CI, 1.05-3.19; P = .03). While the risk of cancer-specific mortality was also elevated (HR, 1.87; P = .09), this trend did not reach statistical significance.

The authors summarized, “In this large cohort of US veterans undergoing treatment for localized prostate cancer, the HSD3B1 CC genotype was associated with inferior oncologic outcomes following definitive radiation therapy with ADT.”

The findings highlight a potential genetic factor that could inform treatment planning for veterans with localized prostate cancer. ADT remains a mainstay of therapy in combination with radiation for many patients; however, the presence of the HSD3B1(1245C) allele may reduce the effectiveness of hormonal suppression by promoting extragonadal androgen synthesis. Identifying patients with this genotype could help clinicians better predict which men are at higher risk for recurrence despite standard therapy.

For providers in the VHA, where precision medicine efforts such as the MVP continue to expand, these data underscore the value of integrating genomic information into clinical decision-making. The study suggests that targeting 3ß-hydroxysteroid dehydrogenase-1 or modifying the androgen-signaling pathway might represent future strategies to improve outcomes in this subgroup.

Ultimately, this large-scale genetic analysis provides strong evidence that the HSD3B1 CC genotype can serve as a predictive biomarker for poor response to combined radiation and ADT, warranting further exploration of tailored therapeutic approaches for affected veterans.

Reference

Morgan KM, Teerlink C, Nelson TJ, et al. Influence of HSD3B1 genotype on prostate cancer outcomes following definitive radiation therapy with androgen deprivation therapy: a retrospective analysis of the Million Veterans Program. Presented at: ASTRO 2025; September 27-October 1; San Francisco, CA.