Aims: Tamoxifen is metabolized by cytochrome P450s, with an important role for CYP2D6. Recently, we demonstrated in 80 patients that CYP2C19*2 is associated with increased survival in breast cancer patients using tamoxifen. Here, we aimed to confirm this in a large group of 499 patients. Materials & methods: A total of 499 estrogen receptor-positive primary breast tumor specimens of advanced disease patients treated with first-line tamoxifen were genotyped for CYP2C19*2 and *17 variant alleles, with primary end point time-to-treatment failure (TTF). Effects of CYP2C19, independent of treatment, were analyzed in 243 primary systematic untreated patients. Results:CYP2C19*2 hetero- and homozygote patients combined showed significantly longer TTFs (hazard ratio [HR]: 0.72; 95% CI: 0.57–0.90; p = 0.004). In multivariate analysis, including CYP2D6*4 status, CYP2C19*2 remained independently associated with TTF (HR: 0.73; 95% CI: 0.58–0.91; p = 0.007). In untreated patients, the CYP2C19*17 allele was significantly associated with a longer disease-free interval (HR: 0.66; 95%CI: 0.46–0.95; p = 0.025). Conclusion:CYP2C19 genotyping is potentially important for tamoxifen therapy for advanced disease and for breast cancer prognosis.

Original submitted 14 February 2011; Revision submitted 8 April 2011

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Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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Published online 15 August 2011

Published in print August 2011

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Acknowledgements

The authors thank Jan Klijn, Louk Beex, Marijke Bontenbal and Andre Uitterlinden for continuous cooperation, and Renske Fles, Iris van Staveren, Kirsten Ruigrok-Ritstier and Henk Portengen for excellent technical support.

Financial & competing interests disclosure

This study was supported by an Erasmus MC Grant MEC 194.305/2000/168A and in part by TI Pharma (Grant number T3–108) and The Netherlands Genomics Initiative (NGI/NOW). The authors have no other relevant affiliations or financial involvements with any organization or entity with a financial interest in or a financial conflict with the subject matter or material discussed in the manuscript apart from the disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients

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The CYP2C192* genotype predicts tamoxifen treatment outcome in advanced breast cancer patients