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Published on: March 6, 2018
Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With
Masaki Shiota1, Shintaro Narita2, Shusuke Akamatsu3
1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Importance:
Recently, genetic polymorphism in HSD3B1 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.
Objective:
To investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone.
Design, Setting, And Participants:
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 HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing.
Exposures:
Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer.
Main Outcomes And Measures:
The association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined.
Results:
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 HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49; P = .03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69; P = .006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94; P = .04) compared with men carrying homozygous wild type.
Conclusions And Relevance:
This study showed that HSD3B1 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.
Insights
The HSD3B1 gene variant impacts prostate cancer outcomes differently depending on treatment. In Japanese men, this genetic variant increases progression risk with androgen-deprivation therapy (ADT) but decreases risk with abiraterone treatment.
Area of Science:
- Oncology
- Genetics
- Pharmacogenomics
Background:
- Genetic variations in HSD3B1 influence prostate cancer outcomes with androgen-deprivation therapy (ADT).
- Abiraterone acetate combined with ADT improves survival, but its interaction with HSD3B1 variants across ethnicities is unclear.
Purpose of the Study:
- To investigate the prognostic significance of HSD3B1 missense polymorphism in Japanese men undergoing primary ADT or abiraterone treatment.
- To evaluate HSD3B1 as a potential predictive biomarker for treatment response in prostate cancer.
Main Methods:
- A prognostic study involving 203 Japanese men with metastatic hormone-sensitive prostate cancer or castration-resistant prostate cancer.
- Genotyping of HSD3B1 (rs1047303, 1245C) was performed using Sanger sequencing on DNA from whole blood samples.
Main Results:
- In the primary ADT cohort, HSD3B1 variant genotypes were associated with a higher risk of progression (HR 2.34) compared to wild-type.
- In the abiraterone cohort, HSD3B1 variant genotypes were associated with a lower risk of progression (HR 0.32) and all-cause mortality (HR 0.40).
Conclusions:
- HSD3B1 genetic variants show distinct associations with oncological outcomes in Japanese men treated with primary ADT versus abiraterone.
- The HSD3B1 gene variant may serve as a predictive biomarker for both ADT and abiraterone efficacy in prostate cancer patients.
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