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Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes

Werner Schroth, Lydia Antoniadou, Peter Fritz, Matthias Schwab, Thomas Muerdter, Ulrich M. Zanger, Wolfgang Simon, Michel Eichelbaum, Hiltrud Brauch

From the Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, the University Tuebingen, and the Robert Bosch Hospital, Stuttgart; and the Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany

Address reprint requests to Hiltrud Brauch, PhD, Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany; e-mail: hiltrud.brauch{at}ikp-stuttgart.de

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.

Supported by the Robert Bosch Foundation, Stuttgart, Germany.

Presented in part as a poster at the First AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development: Maximizing Opportunities for Individualized Treatment, Chicago, IL, September 12-15, 2006.

Ulrich M. Zanger is a named coinventor of pending patent applications directed to the detection of CYP2D6 *41 allele polymorphisms for diagnostic purposes and is entitled to share in any net income derived from licensing these patent rights under standard academic institutional policies.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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