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, Zeruesenay Desta, D. A. Flockhart, Anna Maria Storniolo, V. Stearns, Todd Skaar, D. F. Hayes, N. L. Henry, J. M. Rae

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.The Pharmacogenomics Journal advance online publication, 23 August 2016; doi:10.1038/tpj.2016.60.

Original languageEnglish (US)
JournalPharmacogenomics Journal
DOIs
StateAccepted/In press - Aug 23 2016

Fingerprint

exemestane
Cytochrome P-450 CYP3A
Breast Neoplasms
Enzymes
Pharmaceutical Preparations
Single Nucleotide Polymorphism
Pharmacogenetics
Transaminases
Renal Insufficiency
Publications
Body Mass Index
Pharmacokinetics

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer. / Hertz, D. L.; Kidwell, K. M.; Seewald, N. J.; Gersch, C. L.; Desta, Zeruesenay; Flockhart, D. A.; Storniolo, Anna Maria; Stearns, V.; Skaar, Todd; Hayes, D. F.; Henry, N. L.; Rae, J. M.

In: Pharmacogenomics Journal, 23.08.2016.

Research output: Contribution to journalArticle

Hertz, D. L. ; Kidwell, K. M. ; Seewald, N. J. ; Gersch, C. L. ; Desta, Zeruesenay ; Flockhart, D. A. ; Storniolo, Anna Maria ; Stearns, V. ; Skaar, Todd ; Hayes, D. F. ; Henry, N. L. ; Rae, J. M. / Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer. In: Pharmacogenomics Journal. 2016.
@article{5c47e84757e94e8eb21ffa51bda58e61,
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.The Pharmacogenomics Journal advance online publication, 23 August 2016; doi:10.1038/tpj.2016.60.",
author = "Hertz, {D. L.} and Kidwell, {K. M.} and Seewald, {N. J.} and Gersch, {C. L.} and Zeruesenay Desta and Flockhart, {D. A.} and Storniolo, {Anna Maria} and V. Stearns and Todd Skaar and Hayes, {D. F.} and Henry, {N. L.} and Rae, {J. M.}",
year = "2016",
month = "8",
day = "23",
doi = "10.1038/tpj.2016.60",
language = "English (US)",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer

AU - Hertz, D. L.

AU - Kidwell, K. M.

AU - Seewald, N. J.

AU - Gersch, C. L.

AU - Desta, Zeruesenay

AU - Flockhart, D. A.

AU - Storniolo, Anna Maria

AU - Stearns, V.

AU - Skaar, Todd

AU - Hayes, D. F.

AU - Henry, N. L.

AU - Rae, J. M.

PY - 2016/8/23

Y1 - 2016/8/23

N2 - 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.The Pharmacogenomics Journal advance online publication, 23 August 2016; doi:10.1038/tpj.2016.60.

AB - 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.The Pharmacogenomics Journal advance online publication, 23 August 2016; doi:10.1038/tpj.2016.60.

UR - http://www.scopus.com/inward/record.url?scp=84983434634&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983434634&partnerID=8YFLogxK

U2 - 10.1038/tpj.2016.60

DO - 10.1038/tpj.2016.60

M3 - Article

C2 - 27549341

AN - SCOPUS:84983434634

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

ER -