Simplified phenotyping of CYP2D6 for tamoxifen treatment using the N-desmethyl-tamoxifen/ endoxifen ratio

Abstract

Introduction CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E < 16 nM may relate to worse outcome. Materials and methods A target NDMT/E ratio was defined as associated with an E level of 15 nM in the 161 patient Test cohort of tamoxifen-treated patients, dichotomizing them into ‘Normal’ (NM) and ‘Slow’ (SM) CYP2D6 metabolizer groups. This ratio was then tested on a validation cohort of 52 patients. Patients were phenotyped based on the standard method (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether any variant allele (V) vs wildtype (wt) was present (wt/wt, wt/V, V/V). Comprehensive CYP2D6 genotyping was undertaken on germline DNA. Results A target NDMT/E ratio of 35 correlated with the 15 nM E level, dichotomizing patients into NM (<35; N = 117) and SM (>35; N = 44) groups. The ratio was independently validated by a validation cohort. The simplified system was better in predicting patients without slow metabolism, with specificity and sensitivity of 96% and 44% respectively, compared with the standard method - sensitivity 81% and specificity 83%. Conclusions The simplified classification system based on whether any variant was present better identified patients who were truly not CYP2D6 slow metabolizers more accurately than the current system. However, as CYP2D6 genotype is not the only determinant of endoxifen level, we recommend that direct measurement of endoxifen should also be considered.

Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

“…The second important change concerns the CYP2D6*10 allele, which was downgraded from AS = 0.5, comparable to other decreased activity alleles such as *9 and *41, to AS = 0.25 [38,39]. Most recently, Lee et al suggested a dichotomization into normal and slow metabolizer CYP2D6 groups in an effort to improve and simplify the current system [40]. Nonetheless, these authors also recommend considering the direct measurement of endoxifen plasma concentrations, as CYP2D6 genotype is not solely responsible for systemic endoxifen levels.…”

“…Most recently, Lee et al suggested a dichotomization into normal and slow metabolizer CYP2D6 groups in an effort to improve and simplify the current system [ 40 ]. Nonetheless, these authors also recommend considering the direct measurement of endoxifen plasma concentrations, as CYP2D6 genotype is not solely responsible for systemic endoxifen levels.…”

Pharmacogenetics and pharmacokinetics of tamoxifen in a Zimbabwean breast cancer cohort

“…The endoxifen/NDM‐tamoxifen threshold value used in this study was 0.03. There were 15 patients (37.5%) below this threshold, which were classified as slow metabolizers, while the 62.5% above this ratio were classified as normal metabolizers 24 . Out of the slow metabolizers, 60% were IMs and 40% were NMs according to the CPIC standard classification.…”

“…There were 15 patients (37.5%) below this threshold, which were classified as slow metabolizers, while the 62.5% above this ratio were classified as normal metabolizers. 24 Out of the slow metabolizers, 60% were IMs and 40% were NMs according to the CPIC standard classification. Additionally, 84% of those classified as NMs according to the metabolic ratio were NMs as per CPIC standard classification.…”

Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups

“…At the same time, limitations of genotype-guided initial dose selection exist, such as phenocopying by the concomitant use of certain comedications, which cannot be accounted for by genotyping [ 42 ]. Consequently, recent research suggests that phenotyping instead of genotyping could be more adequate for predicting the extent of endoxifen formation [ 43 , 44 , 45 ] and thus for guiding initial tamoxifen dose selection.…”