Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes.

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.

• Authors: Werner Schroth, Lydia Antoniadou, Peter Fritz, Matthias Schwab, Thomas Muerdter, Ulrich M Zanger, Wolfgang Simon, Michel Eichelbaum, Hiltrud Brauch
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 25 Issue 33 Pg. 5187-93 (Nov 20 2007) ISSN: 1527-7755 [Electronic] United States
• PMID: 18024866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Antagonists
• Tamoxifen
• Mixed Function Oxygenases
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP2D6

Topics

• Adult
• Aged
• Aged, 80 and over
• Aryl Hydrocarbon Hydroxylases (genetics)
• Breast Neoplasms (drug therapy, genetics, mortality)
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP2D6 (genetics)
• Estrogen Antagonists (therapeutic use)
• Female
• Gene Frequency
• Genotype
• Humans
• Middle Aged
• Mixed Function Oxygenases (genetics)
• Pharmacogenetics
• Tamoxifen (metabolism, therapeutic use)