Biomedical Engineering Reference
In-Depth Information
It appears that CYP2D6 is the key enzyme responsible for the generation of endox-
ifen [
171
]. The metabolizing activity of this enzyme is highly polymorphic and varies
considerably within a population and between ethnic groups. This large variability is
partly determined by genetic polymorphisms in the CYP2D6 gene, with over 100
allelic variants identified to date, resulting in different phenotypic patterns [
190,
191
] .
Currently, on the basis of CYP2D6 activity, the population is usually categorized into
four phenotypes including ultrarapid metabolizers (UMs), extensive metabolizers
(EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs).
Actually, CY2D6 gene polymorphisms, associated with null or reduced enzyme
activity, have been reported to negatively influence (in a gene-dose manner) the
blood level of endoxifen in numerous prospective pharmacokinetic studies [
11,
172,
192-
196
]. Some retrospective and prospective studies have shown that CYP2D6
polymorphism was associated with worse clinical outcomes in PMs and IMs patients
in terms of recurrence and disease free survival or BC development in the chemo-
prevention setting [
192,
194,
195,
197-
205
] .
This has prompted the consideration of a potential role for CYP2D6 genotype
testing in patients' management and choice of alternative adjuvant therapy. Whether
genotype-guided tamoxifen administration is a valuable and useful option to opti-
mize antihormonal adjuvant therapy remains, however, controversial, and no clear
consensus has yet been reached regarding the insufficient and somewhat conflicting
retrospective clinical data relating CYP2D6 genotype to tamoxifen efficacy [
206-
210
]. Moreover, large interpatient variability in endoxifen levels still subsists even
after correcting for CYP2D6 status. This remaining variability may depend on one
hand on the activity of other cytochromes (CYP3A4/5, 2 C9, 2 C19, 2B6), phase II
conjugation enzymes (SULT1A1, UGT1A4, 2B7, 1A10, 1A8, 2B15) some of them
known to be polymorphic [
11,
173,
182,
196,
206,
207,
211
], as well as transporters
(other than P-glycoprotein or multidrug resistance-associated protein 2 [MRP2] that
seems to have no or limited impact on tamoxifen and metabolites systemic expo-
sure) [
195,
212-
214
]. On the other hand, environmental factors such as treatment
adherence [
215-
220
] and particularly, interacting co-medications do modulate drug
exposure independent of genetic traits [
10,
11,
172
]. In fact, it is estimated that
20-30 % of patients under tamoxifen therapy are also taking antidepressants. Of
importance are some selective serotonin reuptake inhibitors (SSRIs) with strong
CYP2D6-inhibiting activity, such as paroxetine and fluoxetine, that can be pre-
scribed to treat depression or to alleviate tamoxifen-induced hot flushes. The latter
drugs are known to reduce endoxifen plasma concentration and may therefore be
associated with poorer tamoxifen efficacy [
221-
225
] .
The monitoring of plasma concentration of tamoxifen-active metabolites (mainly
endoxifen) may therefore constitute a better predicting tool for tamoxifen efficacy
than genotype testing. In fact, endoxifen levels correspond to the final phenotypic
trait of patients' drug exposure, accounting for the combined effects of all genetic
polymorphisms, physiological and environmental factors that may affect drug dis-
position and bioactivation.
However, whether the monitoring of endoxifen plasma concentrations in breast
cancer patients would constitute a valid approach to optimize individual dosage and
improve treatment effectiveness remains to be demonstrated. So far, only one study
