Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab

Disclosures

Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article

Tamoxifen Pharmacokinetics & CYP2D6

Within the past decade, there have been numerous pharmacokinetic studies stressing the link between patients' CYP2D6 genotype and its prediction of enzyme function, and plasma levels of active tamoxifen metabolites. Table 3 summarizes such pharmacokinetic studies, which report the correlation between CYP2D6 genotype and plasma endoxifen levels of patients under tamoxifen treatment. Most of these studies were conducted in women with different menopausal statuses. A recent study in postmenopausal women showed a CYP2D6 gene-dose effect in which EMs and UMs had the highest endoxifen concentrations while PMs had the lowest.[19] There is first evidence in premenopausal women that *1/*1 carriers had endoxifen concentrations that were up to 2.4- and 2.6-fold higher than those of *10/*10 and *5/*10 carriers, respectively.[43] Taken together, the correlation between CYP2D6 genetics and plasma endoxifen levels in individuals undergoing tamoxifen therapy is well established (Table 3). By contrast, there is a lack of studies addressing a direct link between tamoxifen metabolite levels and effect on clinical outcome. A first study by Madlensky et al. shows that patients in the lowest quintile of endoxifen plasma concentrations were associated with increased risk of recurrence.[44] This needs further confirmation and there are studies currently underway. Indeed, there is a need to investigate whether monitoring plasma levels under therapy may complement the prediction of CYP2D6 enzyme function and whether this approach may be used as a surrogate for clinical efficiency.

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