Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With  CYP2A6  Genetic Variants, Body Mass Index, and Age | Zendy

Desta Z | Zendy; Kreutz Y | Zendy; Nguyen A T | Zendy; Li L | Zendy; Skaar T | Zendy; Kamdem L K | Zendy; Henry N L | Zendy; Hayes D F | Zendy; Storniolo A M | Zendy; Stearns V | Zendy; Hoffmann E | Zendy; Tyndale R F | Zendy; Flockhart D A | Zendy

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Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age

Author(s) -

Desta Z,

Kreutz Y,

Nguyen A T,

Li L,

Skaar T,

Kamdem L K,

Henry N L,

Hayes D F,

Storniolo A M,

Stearns V,

Hoffmann E,

Tyndale R F,

Flockhart D A

Publication year - 2011

Publication title -

clinical pharmacology and therapeutics

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.941

H-Index - 188

eISSN - 1532-6535

pISSN - 0009-9236

DOI - 10.1038/clpt.2011.174

Subject(s) - letrozole , cyp2a6 , medicine , breast cancer , exemestane , pharmacogenomics , pharmacogenetics , body mass index , pharmacology , oncology , aromatase inhibitor , endocrinology , aromatase , genotype , cancer , biology , genetics , metabolism , cyp1a2 , gene , cytochrome p450

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. Clinical Pharmacology & Therapeutics (2011); 90 5, 693–700. doi: 10.1038/clpt.2011.174

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