title: Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer.
abstract: Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% greater exemestane concentration (P<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index and had not received chemotherapy (all P<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (P<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.
authors.affiliation: Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Hertz
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Kidwell
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Seewald
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Gersch
authors.affiliation: Department of Medicine, Indiana University, Bloomington, IN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Department of Medicine, Indiana University, Bloomington, IN, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Department of Medicine, Indiana University, Bloomington, IN, USA.
authors.forename: A-M
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Department of Medicine, Indiana University, Bloomington, IN, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Henry
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Rae
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008875:Middle Aged; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D057285:Precision Medicine; D011237:Predictive Value of Tests
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C056516:exemestane