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


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.


CONCLUSIONS
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.
Schroth
Werner
W
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. hiltrud.brauch@ikp-stuttgart.de
Antoniadou
Lydia
L
Fritz
Peter
P
Schwab
Matthias
M
Muerdter
Thomas
T
Zanger
Ulrich M
UM
Simon
Wolfgang
W
Eichelbaum
Michel
M
Brauch
Hiltrud
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D013629:Tamoxifen / Q000378:metabolism / Q000627:therapeutic use*
D004965:Estrogen Antagonists; D013629:Tamoxifen; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6