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Missense Polymorphism in SRD5A2 in Combination with HSD3B1 Variation Is Associated with Outcome of Castration-Resistant Prostate Cancer Patients Treated with Abiraterone
31 Pages Posted: 13 Jul 2020
More...Abstract
Background: Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone.
Methods: A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758) and AKR1C3 (rs12529) was performed by PCR-based technique.
Findings: Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20–0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17–0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.
Funding Statement: This work was supported by a JSPS KAKENHI grant (17K11145) to M.S.
Declaration of Interests: MS, SA, SN, OO, TH and ME received honoraria from Janssen Pharmaceutical. The other authors declare no conflict of interest.
Ethics Approval Statement: This study was performed in accordance with the principles described in the Declaration of Helsinki and the Ethical Guidelines for Epidemiological Research enacted by the Japanese Government and approved by each institutional review board. Written informed consent was obtained from all patients.
Keywords: abiraterone; androgen synthesis; HSD3B1; SNP; SRD5A2
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