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Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Mwinyi, Jessica ; Vokinger, Kerstin ; Jetter, Alexander ; Breitenstein, Urs ; Hiller, Christian ; Kullak-Ublick, Gerd ; Trojan, Andreas

In: Cancer Chemotherapy and Pharmacology, 2014, vol. 73, no. 6, p. 1181-1188

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    Titre
    • Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy
    Auteur
    • Mwinyi, Jessica. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    • Vokinger, Kerstin. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    • Jetter, Alexander. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    • Breitenstein, Urs. Breast Center Zürich, Zurich, Switzerland
    • Hiller, Christian. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    • Kullak-Ublick, Gerd. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    • Trojan, Andreas. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Cancer Chemotherapy and Pharmacology, 2014, vol. 73, no. 6, p. 1181-1188. Springer Berlin Heidelberg
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:325148
    Summary
    Background: Tamoxifen is frequently used for the treatment of hormone receptor positive breast cancer (BC). Mainly CYP2D6 is responsible for the transformation to therapeutically active metabolites, but CYP2C19, CYP2C9 and CYP2B6 also are involved. We investigated the impact of polymorphisms within the genes encoding these CYP enzymes on the relapse-free time (RFT) in patients with BC. Methods: Ninety-nine patients with hormone receptor positive BC, who had undergone adjuvant tamoxifen therapy, were genotyped for seventeen common variants within the genes encoding CYP2D6, CYP2C9, CYP2C19 and CYP2B6 using TaqMan and PCR-RFLP technology. Kaplan-Meier and Cox regression analyses were performed to elucidate the impact of genetic variants on RFT. Furthermore, CYP2D6 metabolic activity was determined in a subset of 50 patients by assessing dextromethorphan/dextrorphan urinary excretion ratios. CYP2D6 activity was compared to the CYP2D6 allelic combinations to evaluate the predictive value of the CYP2D6 genotyping results on phenotype. Results: Although a trend toward longer RFTs in carriers of CYP2D6 allele combinations encoding for extensive and ultrafast metabolizer phenotypes was observed, none of the investigated genetic variants had a statistically significant impact on RFT. The combined analysis of five major CYP2D6 variants was useful for the discrimination between poor and non-poor metabolizers. Conclusions: Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity. Common variants in CYP2C9, CYP2C19, CYP2D6, and CYP2B6 did not have a significant impact on the RFT in this cohort of patients with BC.