Abstract P5-11-04: Phenotype-Genotype Correlations in Breast Cancer Patients Treated with Tamoxifen

Autor: Birthe Schubert, Anne Oberguggenberger, Michael Hubalek, Verena Meraner, B Beer, Barbara Sperner-Unterweger, Herbert Oberacher
Rok vydání: 2010
Předmět:
Zdroj: Cancer Research. 70:P5-11
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.sabcs10-p5-11-04
Popis: Background: Personalized medicine strategies are especially relevant for drugs which show a high inter-individual variability regarding their pharmacokinetic and -dynamic properties. Considerable inter-patient variations have been described regarding the plasma concentrations of tamoxifen and its metabolites. Due to the observation that tamoxifen metabolites can show a high pharmacological activity, tamoxifen metabolism has received considerable attention. The metabolism of tamoxifen is complex resulting in a huge number of different products. Important metabolic transformation reactions include demethylation catalyzed by Cytochrome P450 3A4 and hydroxylation mainly catalyzed by Cytochrome P450 2D6 (CYP2D6). The impact of the CYP2D6 activity, which can be predicted from genetic information, on plasma levels and the related pharmacological effects has controversially been discussed. To get a better understanding of the inter-individual differences of the plasma levels of tamoxifen and some of its metabolites we have used liquid chromatography-tandem mass spectrometry (LC/MS/MS) to screen the plasma samples of 106 breast cancer patients. This method enabled the quantification of tamoxifen as well as a relative quantification of demethyltamoxifen and hydroxylated tamoxifen metabolites. To study the impact of enzyme activity on plasma levels, CYP2D6 genotypes were determined as well. Material and methods: For metabolic profiling 1 ml plasma was treated with a solid phase extraction procedure. Chromatographic separation was accomplished on a reversed-phase column. Analytes were detected by mass spectrometry. For genotyping, the CYP2D6 gene was amplified by a long range PCR followed by a multiplexed PCR to generate specific short amplicons. The amplicons were directly analysed by LC/MS. The information necessary to determine the allelic state were obtained from the measured molecular masses. Results: We determined the CYP2D6 genotype of 106 breast cancer patients treated with tamoxifen. We found 19% “Poor Metabolizers", 51% “Intermediate Metabolizers", 29% “Extensive Metabolizers” and 7% “Ultrarapid Metabolizers”. The observed plasma concentrations of tamoxifen and its metabolites showed a high inter-patient variability For instance, plasma concentrations between 26-307 ng/ml (mean 125 ng/ml) were observed for tamoxifen. We did not find a significant impact of the CYP2D6 status on tamoxifen plasma levels. However, the demethyltamoxifen/tamoxifen as well as the hydroxytamoxifen/tamoxifen ratios appear to be influenced by the CYP2D6 status: the higher the metabolic activity, the higher the hydroxytamoxifen content and the lower the demethyltamoxifen content. Conclusions: We have developed analytical tools, which allow the determination of the content of tamoxifen and its major metabolites in human plasma and the genotyping of the CYP2D6 gene. Phenotypic and genotypic data of 106 patients were acquired. Correlation of the data revealed that the genotype had no significant impact on tamoxifen plasma levels. Nevertheless, patients with a predicted higher CYP2D6 activity showed lower demethyltamoxifen/tamoxifen ratios as well as higher hydroxytamoxifen/tamoxifen ratios. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-04.
Databáze: OpenAIRE
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