Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer

D. L. Hertz, K. M. Kidwell, N. J. Seewald, C. L. Gersch, Z. Desta, D. A. Flockhart, A. M. Storniolo, V. Stearns, T. C. Skaar, D. F. Hayes, N. L. Henry, J. M. Rae

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)521-527
Number of pages7
JournalPharmacogenomics Journal
Volume17
Issue number6
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Fingerprint Dive into the research topics of 'Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer'. Together they form a unique fingerprint.

Cite this