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

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. 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. 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%. 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.

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Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest Clara Inkyung Lee, Peter Fox, Bavanthi Balakrishnar, Bo Gao, Sally Coulter, Christopher Liddle, Mark Wong, and Nicholas Wilcken have no conflicts of interest to declare. Rina Hui has conflicts to declare including: Advisory board member for Merck Sharp and Dohme, Astra Zeneca, Novartis, Roche and Bristol-Myers Squib, speaker honorarium for Merk Sharp and Dohme. Howard Gurney has conflicts to declare including: Advisory board/consulting role for Bristol-Myers Squib, Ipsen, Merck Sharp and Dohme, Astra Zeneca, Janssen-Cilag. Honorarium for Pfizer. Ron H.J. Mathijssen has conflicts to declare including: Speakers’ Bureau: Novartis. Research Funding: Roche (Inst), Sanofi (Inst), Astellas Pharma (Inst), Bayer Holding (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Cristal Therapeutics (Inst), Pamgene (Inst). Travel, Accommodations, Expenses: Pfizer, Astellas Pharma. Stijn L.W. Koolen has conflicts to declare including: Speakers’ Bureau: Novartis, Pfizer, Research Funding: Cristal Therapeutics (Inst), Novartis (Inst), Travel, Accommodations, Expenses: Ipsen.