Clinical Pharmacology & Therapeutics - CYP2D6 Genotype and Tamoxifen Activity: Understanding Interstudy Variability in Methodological Quality

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Clinical Pharmacology & Therapeutics - CYP2D6 Genotype and Tamoxifen Activity: Understanding Interstudy Variability in Methodological Quality

Clinical Pharmacology & Therapeutics (2013); 94 2, 185–187. doi:10.1038/clpt.2013.66

CYP2D6 Genotype and Tamoxifen Activity: Understanding Interstudy Variability in Methodological Quality

M J Ratain^1,2,3, Y Nakamura^1,2,3,4 and N J Cox^1,2,3,5

1. ¹Department of Medicine, The University of Chicago, Chicago, Illinois, USA
2. ²Center for Personalized Therapeutics, The University of Chicago, Chicago, Illinois, USA
3. ³Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, USA
4. ⁴Department of Surgery, The University of Chicago, Chicago, Illinois, USA
5. ⁵Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA

Correspondence: MJ Ratain, (mratain@medicine.bsd.uchicago.edu)

There has been great controversy over the years regarding the impact of CYP2D6 polymorphisms on the efficacy of tamoxifen in women with breast cancer. The most significant publication to date is the report by investigators in Stuttgart, Germany, and at the Mayo Clinic of a 1,325-patient study, published in 2009 in the Journal of the American Medical Association.¹ Despite this high-impact publication, there has been variable acceptance of these findings because of inconsistent replication of the results.²

The controversy

Are the studies demonstrating an association between CYP2D6 genotype and tamoxifen efficacy false-positive studies? We acknowledge that false-positive studies are endemic in the pharmacogenomic literature, generally because of failure to correct for multiple testing of associations between a large number of candidate polymorphisms and multiple phenotypes. However, this concern is not applicable to the study by Schroth and colleagues¹ or most of the other positive studies that have focused exclusively on testing of a single polymorphic gene, CYP2D6. Furthermore, although some of these positive studies have modest sample sizes and/or incomplete genotyping, those factors would not affect the probability that a positive study is a true positive (but would increase the probability of a false-negative study).

Or are the studies that failed to demonstrate such an association false-negative studies? If so, what would be the explanation? False-negative replication studies can occur for many reasons. One often focuses on statistical explanations for failure of replication. For example, studies may be too small to detect the hypothesized effect, or the true effect may be less than was previously observed, a phenomenon known as “the winner’s curse.” Even large studies may fail to replicate as a result of statistical issues, as the type 2 error can never be zero. However, we believe that the multiple negative studies of CYP2D6 and tamoxifen exemplify more fundamental issues in pharmacogenomics that are particularly relevant to studies in cancer patients.