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Controlled Clinical Trial
. 2009 Aug;9(4):258-64.
doi: 10.1038/tpj.2009.14. Epub 2009 May 5.

Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients

J M Rae  1 , M J Sikora, N L Henry, L Li, S Kim, S Oesterreich, T C Skaar, A T Nguyen, Z Desta, A M Storniolo, D A Flockhart, D F Hayes, V Stearns; COBRA investigators
Affiliations
Controlled Clinical Trial

Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients

J M Rae et al. Pharmacogenomics J. 2009 Aug.

Abstract

The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen-receptor-positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n=297) were genotyped for CYP2D6 variants and assigned a 'score' based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months was tested. We observed a strong nonlinear correlation between higher CYP2D6 score and increased rates of discontinuation (r(2)=0.935, P=0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely.

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Conflict of interest statement

Conflicts of interest:

JMR has received research funding Pfizer and speaking honoraria for Roche Diagnostics.

TS has received speaking honoraria for Roche Diagnostics.

DAF is on the Scientific Advisory Board of Labcorp, Inc, is a consultant to Roche Molecular Diagnostics, and has received research funding from Pfizer and Novartis.

DFH has received research funding from AstraZeneca, Glaxo-Smith Kline, Pfizer, and Novartis.

VS has served as a consultant to Wyeth Pharmaceuticals, Concert Pharmaceuticals and JDS Pharmaceuticals, and has received research funding from Glaxo-Smith Kline, Pfizer, and Novartis.

Figures

Figure 1
Figure 1
Consort diagram of tamoxifen trial population. Patients who continued study participation for at least 4 months (n = 239) or discontinued study participation for tamoxifen-related side effects (n = 28) were analyzed for associations between CYP2D6 genotype and treatment discontinuation (n = 267).
Figure 2
Figure 2
CYP2D6 genotype is a predictor of tamoxifen discontinuation. Data shown as percentage of patients with CYP2D6 score that discontinued treatment due to tamoxifen-related side effects. Non-linear Michaelis-Menten modeling of CYP2D6 score based on genotype (A) or adjusted for concomitant medications (B).
See this image and copyright information in PMC

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