HSD3B1 Variants Linked With Outcomes of Prostate Cancer Treatments

HSD3B1 genotype may be a predictive biomarker for the use of androgen deprivation therapy (ADT) or abiraterone in Japanese men with prostate cancer, according to a recent study.

In the retrospective study, genetic variation in HSD3B1 was associated with worse outcomes of ADT in men with hormone-sensitive prostate cancer, but with improved outcomes with abiraterone in patients with castration-resistant prostate cancer (CRPC), reported Masaki Shiota, MD, PhD, of Kyushu University in Japan, and colleagues, in a study published in JAMA Network Open.

“Recent studies have demonstrated that genetic polymorphism in HSD3B1 is associated with oncological outcome among residents in the United States treated with ADT, where men carrying variant alleles showed worse prognosis,” Shiota and colleagues explained. “Thus, genetic variation in HSD3B1 (1245C) genotype is a promising predictive biomarker of positive ADT response among men with prostate cancer. However, its impact on prognosis among people of different ethnicities remains unclear.”

The Japanese study included two groups of patients: 104 men with metastatic hormone-sensitive prostate cancer treated with ADT from 1993 to 2005 and 99 men with CRPC treated with abiraterone from 2014 to 2018. DNA was obtained from blood samples, and genotyping on HSD3B1 was performed by Sanger sequencing.

In the primary ADT cohort, the majority of men were homozygous wild-type (91.3%), with smaller percentages having the heterozygous variant type (6.7%) and the homozygous variant type (1.9%).

Among men being treated with ADT, those with heterozygous and homozygous variant types in the HSD3B1 gene had more than double the risk for progression (hazard ratio [HR], 2.35; 95% CI, 1.08–4.49; P = .03) compared with men with homozygous wild-type, but no additional risk for any-cause death (HR, 1.36; 95% CI, 0.52–2.92; P = .50).

In contrast, among the men treated with abiraterone, those with variant type in the HSD3B1 gene (14.1%) had significantly lower risk for progression (HR, 0.32; 95% CI, 0.12–0.69; P = .006) and all-cause mortality (HR, 0.40; 95% CI, 0.13–0.94; P = .04) compared with men with homozygous wild-type (85.9%).

“Recently, upfront abiraterone treatment was shown to improve survival in metastatic hormone-sensitive prostate cancer by the LATITUDE and STAMPEDE trials, although a predictive biomarker was not identified so far,” the researchers wrote. “According to the result in the current study, men carrying variant type in HSD3B1 gene may be suitable candidates for upfront abiraterone treatment even in a low-risk group because their tumors would be resistant to ADT but vulnerable to abiraterone.”

Commenting on the paper, Nima Sharifi, MD, director of the Genitourinary Malignancies Research Center at Cleveland Clinic, told Cancer Network that the current paper clearly shows that whether or not the HSD3B1 germline variant is present affects response duration for hormonal therapy.

“This means that the predictive value of this variant as a biomarker shown in other studies done previously in patient cohorts in the United States also applies to Japanese patients,” Sharifi said.

Sharifi and colleagues first showed this in a 2016 Lancet Oncologypaper studying 443 men.

“Because the HSD3B1 germline variant frequency varies significantly in patients from different racial background, it might help account for differential treatment response to hormonal therapy in patients from different racial groups,” Sharifi said.