Association of Missense Polymorphism in<i>HSD3B1</i>With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone

Abstract

<h3>Importance</h3> Recently, genetic polymorphism in<i>HSD3B1</i>encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear. <h3>Objective</h3> To investigate the significance of missense polymorphism in<i>HSD3B1</i>gene among men treated with primary ADT or abiraterone. <h3>Design, Setting, and Participants</h3> This prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on<i>HSD3B1</i>(rs1047303, 1245C) was performed by Sanger sequencing. <h3>Exposures</h3> Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer. <h3>Main Outcomes and Measures</h3> The association of genotype in<i>HSD3B1</i>with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure–free survival, and overall survival was examined. <h3>Results</h3> Of 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in<i>HSD3B1</i>gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49;<i>P</i> = .03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92;<i>P</i> = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in<i>HSD3B1</i>gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69;<i>P</i> = .006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94;<i>P</i> = .04) compared with men carrying homozygous wild type. <h3>Conclusions and Relevance</h3> This study showed that<i>HSD3B1</i>genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.