Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles
| Autor: | Espen Molden, Linda Thorén, Jonas Bergh, Per Hall, Sara Margolin, Erik Eliasson, Marianne Kristiansen Kringen, Jonatan D. Lindh, Gerd Ackehed |
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| Rok vydání: | 2020 |
| Předmět: |
Oncology
medicine.medical_specialty CYP2D6 Antineoplastic Agents Hormonal Genotype Breast Neoplasms digestive system 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine Breast cancer Internal medicine Humans Medicine Pharmacology (medical) 030212 general & internal medicine Allele skin and connective tissue diseases Genotyping Alleles Retrospective Studies Pharmacology Endoxifen business.industry medicine.disease Tamoxifen Cytochrome P-450 CYP2D6 Female business Pharmacogenetics medicine.drug |
| Zdroj: | British Journal of Clinical Pharmacology. 87:1243-1252 |
| ISSN: | 1365-2125 0306-5251 |
| Popis: | AIMS Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels |
| Databáze: | OpenAIRE |
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