Dr Oesterheld's Comment: It has been well established that women with breast cancer who may receive tamoxifen should receive genetic CYP2D6 testing. They may be in a group of individuals who will not receive benefit from tamoxifen because they are slow metabolizers and will not convert the pro-drug tamoxifen to the active metabolite endoxifen which is responsible for the oncologic action. This abstract goes a step further in suggesting that CYP2C19 testing would also benefit these women because it predicts those who are likely to have the best outcomes with tamoxifen.

J Clin Oncol. 2007 Nov 20;25(33):5187-93.

Comment in:

J Clin Oncol. 2007 Nov 20;25(33):5147-9.

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

Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H.

Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. hiltrud.brauch@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.

PMID: 18024866