Westmead Hospital, Sydney, Australia
Clara Inkyung Lee , Amanda Siew Kee Low , Peter Fox , Bavanthi Balakrishnar , Rosemary L Balleine , Bo Gao , Pamela Provan , Sally Coulter , Christopher Liddle , Rina Hui , Nicholas Wilcken , Mark Wong , Howard Gurney
Background: Classifications for CYP2D6 phenotypes are established for debrisoquine, sparteine and codeine, but not for tamoxifen. CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (EDF). CYP2D6polymorphisms are common and can affect CYP2D6 protein activity and EDF level. Retrospective analyses of two breast cancer studies indicate that EDF levels below 15nM may relate to worse outcome. Methods: A target NDMT/EDF ratio was defined as that which was associated with an EDF level of 15nM in 108 Australian tamoxifen-treated patients (pts), dichotomizing the group into ‘Normal’ (NM) and ‘Slow’ CYP2D6 metabolizer groups (SM). Pts were classified according to genotype based on Crews et al Clin Pharmacol Ther 95, 376, 2014 (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether anyvariant allele was present. The following alleles were measured: *2, *3, *4, *5, *6, *8, *9, *10, *14, *17, *39, *41, 1N and 2N on germline DNA. Concomitant CYP2D6 inhibitor use was excluded. Results: A target NDMT/EDF ratio of 44 correlated with 15nM EDF level and dichotomized pts into NM (<44; N =90) and SM (>44; N= 18) groups. Association between classification systems and slow metabolizer status is shown in table below. Conclusions: If validated, this simple classification system may be superior to standard systems for predicating slow CYP2D6 metabolism. However, a significant proportion of v/v patients (26%) had normal CYP2D6 activity indicating that CYP2D6 genotype may be a poor measure of protein activity and that direct measurement of endoxifen should be considered.
Current genotype classification | Simplified classification | |||||
---|---|---|---|---|---|---|
UM/EM N = 91 | IM N = 9 | PM N = 8 | wt/wt N = 44 | wt/v N = 41 | v/v N = 23 | |
Slow metabolizer (NDMT/EDF > 44) N = 18 | 5/91 (5%) | 5/9 (56%) | 8/8 (100%) | 0/44 (0%) | 1/41 (2%) | 17/23 (74%) |
Sensitivity | 44.4% | 94.4% | ||||
Specificity | 100% | 93.3% | ||||
Sensitivity | 72.2% | |||||
Specificity | 95.6% |
v/v pts were further examined but no single allele predicted for SM with many alleles occurring in both SM and NM pts.
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Abstract Disclosures
2011 ASCO Annual Meeting
First Author: M. E. B. Welzen
2020 ASCO Virtual Scientific Program
First Author: Andrea De Censi
2018 ASCO Annual Meeting
First Author: Toshimi Takano
2012 ASCO Annual Meeting
First Author: Bavanthi Balakrishnar