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https://hdl.handle.net/2440/44528
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Type: | Journal article |
Title: | Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes |
Author: | Schroth, W. Antoniadou, L. Fritz, P. Schwab, M. Muerdter, T. Zanger, U. Simon, W. Eichelbaum, M. Brauch, H. |
Citation: | Journal of Clinical Oncology, 2007; 25(33):5187-5193 |
Publisher: | Amer Soc Clinical Oncology |
Issue Date: | 2007 |
ISSN: | 0732-183X 1527-7755 |
Statement of Responsibility: | Werner Schroth, Lydia Antoniadou, Peter Fritz, Matthias Schwab, Thomas Muerdter, Ulrich M. Zanger, Wolfgang Simon, Michel Eichelbaum, Hiltrud Brauch |
Abstract: | Purpose: The clinical outcome of tamoxifen-treated breast cancer patients may be influenced by the activity of cytochrome P450 enzymes that catalyze the formation of antiestrogenic metabolites endoxifen and 4-hydroxytamoxifen. We investigated the predictive value of genetic variants of CYP2D6, CYP2C19, and three other cytochrome P450 enzymes for tamoxifen treatment outcome. Patients and Methods: DNA from 206 patients receiving adjuvant tamoxifen monotherapy and from 280 patients not receiving tamoxifen therapy (71 months median follow-up) was isolated from archival material and was genotyped for 16 polymorphisms of CYP2D6, CYP2C19, CYP2B6, CYP2C9, and CYP3A5 by matrix-assisted, laser desorption/ionization, time-of-flight mass spectrometry, and by copy number quantification. Risk and survival estimates were calculated using logistic regression, Kaplan-Meier, and Cox regression analyses. Results: Tamoxifen-treated patients carrying the CYP2D6 alleles *4, *5, *10, *41—all associated with impaired formation of antiestrogenic metabolites—had significantly more recurrences of breast cancer, shorter relapse-free periods (hazard ratio [HR], 2.24; 95% CI, 1.16 to 4.33; P = .02), and worse event-free survival rates (HR, 1.89; 95% CI, 1.10 to 3.25; P = .02) compared with carriers of functional alleles. Patients with the CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical outcome (HR, 0.45; 95% CI, 0.21 to 0.92; P = .03) than carriers of *1, *2, and *3 alleles. Conclusion: Because genetically determined, impaired tamoxifen metabolism results in worse treatment outcomes, genotyping for CYP2D6 alleles *4, *5, *10, and *41 can identify patients who will have little benefit from adjuvant tamoxifen therapy. In addition to functional CYP2D6 alleles, the CYP2C19 *17 variant identifies patients likely to benefit from tamoxifen. |
Keywords: | Humans Breast Neoplasms Tamoxifen Estrogen Antagonists Aryl Hydrocarbon Hydroxylases Cytochrome P-450 CYP2D6 Mixed Function Oxygenases Pharmacogenetics Gene Frequency Genotype Adult Aged Aged, 80 and over Middle Aged Female Cytochrome P-450 CYP2C19 |
Description: | © 2007 American Society of Clinical Oncology. |
DOI: | 10.1200/JCO.2007.12.2705 |
Published version: | http://dx.doi.org/10.1200/jco.2007.12.2705 |
Appears in Collections: | Aurora harvest 6 Pharmacology publications |
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