Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

Abstract

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy.

TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration‐Resistant Prostate Cancer

“…To determine whether the TSPYL1 rs3828743 SNP was associated with abiraterone response in prostate cancer patients, we used data from a prospective clinical trial involving 89 patients with metastatic CRPC who had been treated with abiraterone acetate/prednisone (AA/P) . Of 89 patients recruited, 87 patients had information available for their initial response to AA/P.…”

“…Since the CYP17A1 rs2486758 SNP has been reported to be associated with the outcome of AA/P treatment in prostate cancer patients, and since this CYP17A1 SNP maps to the TSPYL1/2/4 binding sites within the promoter region (Supplemental Figure 4d ), we also determined whether this SNP might affect TSPYL1/2/4 binding to the CYP17A1 promoter. DNA fragments of CYP17A1 promoter containing either WT or variant CYP17A1 rs2486758 SNP genotypes were inserted into a luciferase reporter gene construct and luciferase activity was measured.…”

<em>CYP17 </em>polymorphisms are associated with decreased risk of breast cancer in Chinese Han women: a case&ndash;control study

“… 30 As shown in our study, there was also no association between rs2486758 and any clinical characteristics of BC, which is consistent with the previously mentioned study. Mechanistically, the risk of prostate cancer is based on the location of rs2486758 in the promoter region of CYP17 A1, 31 while there was no other study to prove the relation between CYP17 rs2486758 and BC, we considered CYP17 rs2486758 was not affect the transcription of genes.…”

Combined abiraterone acetate plus prednisone, salvage prostate bed radiotherapy and LH-RH agonists (CARLHA-GEP12) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP

“…The mode of administration of abiraterone acetate was similar in all patients. Abiraterone acetate plus prednisone’s efficacy might be affected by CYP17A1 polymorphism [ 17 , 18 ], but no specific profile could be determined in the 2 patients who did not achieve castration levels of testosterone. In general, the pharmacogenetics translational study was inconclusive.…”