Pitfalls and shortcomings of pharmacogenomic association studies: The tamoxifen controversy

author: Hiltrud Brauch, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP)
published: July 21, 2014,   recorded: May 2014,   views: 1663


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The Cytochrome P450 2D6 enzyme has been linked with tamoxifen outcome based on its role to convert the parent drug into active metabolites 4-hydroxytamoxifen and endoxifen and in particular because of its high inter-individual variability of enzyme activity. Impaired CYP2D6 metabolism can be accurately predicted by loss and reduced-function alleles resulting in poor metabolizer (PM) and intermediate metabolizer (IM) phenotypes and likewise functional and duplicated CYP2D6 alleles correlate with extensive (EM) and ultra-rapid (UM) metabolizer phenotypes. Accordingly, the CYP2D6 polymorphism should be relevant to millions of women because tamoxifen is a standard-of-care for the treatment of hormone-receptor positive breast cancer of all stages, and moreover is approved for the chemoprevention of women at high risk to develop breast cancer both in the USA and UK. We recently provided supportive evidence for the hypothesis that impaired CYP2D6 activity is associated with worse tamoxifen outcome in postmenopausal, hormone receptor-positive early breast cancer. In a large retrospective cohort of patients who had received mono tamoxifen for the control of their disease, patients with two functional CYP2D6 alleles showed a better clinical outcome than those with non-functional or reduced function alleles [HR 1.33; 95% CI 1.06-1.68, Schroth et al JAMA 2009]. The finding was challenged by null associations reported from two pharmacogenetic studies of the Breast International Group (BIG) 1-98 and the Arimidex, Tamoxifen Alone or in Combination (ATAC) studies (Regan et al JNCI 2012; Rae et al JNCI 2012). Their patients were prospectively recruited within the context of previous randomized clinical trials and therefore selection bias should be minimal. Yet, a metaanalysis using the globally available datasets of CYP2D6 and tamoxifen outcome as well as a new independent study using prospectively collected patients of the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG8) confirmed the CYP2D6 genotype being associated with a higher risk of recurrence (Province et al CPT 2013, Goetz et al Clin Cancer Res 2013). In my talk, I will revisit the hypothesis of CYP2D6 being a potential outcome predictor of tamoxifen and provide insight into the ongoing controversy that prevented the CYP2D6 marker from being accepted by the scientific and clinical community. I will also show novel pharmacokinetic and pharmacogenetic data from premenopausal patients and summarize the available evidence to explain why study design factors and technical errors may obscure the utility of the CYP2D6 genotype.

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