title: 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.
authors.affiliation: Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Binder.Moritz@mayo.edu.
authors.forename: Moritz
authors.initials: M
authors.lastname: Binder
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Zhang.Ben@mayo.edu.
authors.forename: Ben Y
authors.initials: BY
authors.lastname: Zhang
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Hillman.David@mayo.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Hillman
authors.affiliation: Mayo High School, 1420 11th Avenue SE, Rochester, MN 55904, USA. rheak99@gmail.com.
authors.forename: Rhea
authors.initials: R
authors.lastname: Kohli
authors.affiliation: Mayo High School, 1420 11th Avenue SE, Rochester, MN 55904, USA. tankoh98@gmail.com.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Kohli
authors.affiliation: Experimental and Clinical Pharmacology Department, University of Minnesota, 515 Delaware St. SE, Minneapolis, MN 55455, USA. leeam@umn.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Kohli.Manish@mayo.edu.
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
mesh_terms: D000069501:Abiraterone Acetate / Q000627:therapeutic use*; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018450:Disease Progression; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011241:Prednisone / Q000627:therapeutic use; D016016:Proportional Hazards Models; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate; D011241:Prednisone
keywords: CYP17A1; abiraterone acetate; metastatic castration-resistant prostate cancer; predictive biomarker; single nucleotide polymorphism