Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age

Zeruesenay Desta, Y. Kreutz, A. T. Nguyen, L. Li, Todd Skaar, L. K. Kamdem, N. L. Henry, D. F. Hayes, Anna Maria Storniolo, V. Stearns, E. Hoffmann, R. F. Tyndale, D. A. Flockhart

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Abstract

The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (10-fold) and were associated significantly with CYP2A6 genotypes (P 0.0001), body mass index (BMI) (P 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.

Original languageEnglish
Pages (from-to)693-700
Number of pages8
JournalClinical Pharmacology and Therapeutics
Volume90
Issue number5
DOIs
StatePublished - Nov 2011

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letrozole
exemestane
Body Mass Index
Breast Neoplasms
Cytochrome P-450 CYP3A
Pharmacogenetics
Genotype

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. / Desta, Zeruesenay; Kreutz, Y.; Nguyen, A. T.; Li, L.; Skaar, Todd; Kamdem, L. K.; Henry, N. L.; Hayes, D. F.; Storniolo, Anna Maria; Stearns, V.; Hoffmann, E.; Tyndale, R. F.; Flockhart, D. A.

In: Clinical Pharmacology and Therapeutics, Vol. 90, No. 5, 11.2011, p. 693-700.

Research output: Contribution to journalArticle

Desta, Zeruesenay ; Kreutz, Y. ; Nguyen, A. T. ; Li, L. ; Skaar, Todd ; Kamdem, L. K. ; Henry, N. L. ; Hayes, D. F. ; Storniolo, Anna Maria ; Stearns, V. ; Hoffmann, E. ; Tyndale, R. F. ; Flockhart, D. A. / Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. In: Clinical Pharmacology and Therapeutics. 2011 ; Vol. 90, No. 5. pp. 693-700.
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abstract = "The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (10-fold) and were associated significantly with CYP2A6 genotypes (P 0.0001), body mass index (BMI) (P 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.",
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