Tamoxifen pharmacogenetics and pharmacokinetics in early-breast cancer
- A.B. Sanchez Spitman
- donderdag 18 februari 2021
2311 GJ Leiden
For more than 40 years, the selective estrogen receptor modulator (SERM) tamoxifen has been the cornerstone of the endocrine therapy for both early and metastatic hormone receptor positive breast cancer cases. However, a wide variability in response to therapy is still observed since disease recurrence happens in nearly 30 % of breast cancer patients. Tamoxifen has a complex metabolism and it is mainly metabolized by CYP2D6 enzyme, among others, into endoxifen, the most active metabolite of tamoxifen. CYP2D6 enzyme is encoded by the highly polymorphic CYP2D6 gene. To date, there are many variants that encode for fully functional or non-functional alleles, or variations with decreased enzymatic activity. At the same time, individuals can be classified in different CYP2D6 phenotypes according to the combinations of these variants. Commonly, patients can be categorized in four CYP2D6 phenotypes: ultrarapid metabolizer (UM), normal metabolizer (NM; which previously was known as extensive metabolized (EM)), intermediate metabolizer (IM) and poor metabolizer (PM).
In the search of a manner in order to individualize endocrine therapy with tamoxifen, CYP2D6 genotyping was proposed as a potential tool. In fact, the association between clinical survival outcomes and the role of CYP2D6 polymorphisms in breast cancer patients receiving tamoxifen has been an ongoing discussion and many studies have been published claiming both negative and positive associations. In theory, CYP2D6 PM and IM patients reach lower endoxifen concentrations due to the decreased or nearly absent CYP2D6 enzymatic activity. Consequently, these individuals are supposed to have a higher probability of breast cancer relapse due to the lower anti-estrogenic exposure (e.g. lower endoxifen concentrations) compared to NM (formerly EM).
This thesis focusses on assessing the influence of diverse genetic variations involved in tamoxifen metabolism, defined as concentrations and metabolic ratios (MRs), and their impact on clinical survival outcome in early-breast cancer patients treated with tamoxifen. Additionally, we also investigated the effect of relevant polymorphisms tamoxifen metabolic pathway on the explained variability between patients.
- Prof.dr. H.J. Guchelaar
- Prof.dr. H. Gelderblom
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