Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia; Department of Medical Oncology, Bankstown-Lidcombe Hospital, Bankstown, Australia; Faculty of Medicine, University of New South Wales, Australia.
Sydney Medical School, University of Sydney, Camperdown, Australia.
Breast. 2020 Dec;54:229-234. doi: 10.1016/j.breast.2020.10.008. Epub 2020 Oct 21.
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.
CYP2D6 蛋白活性可通过 N-去甲基他莫昔芬（NDMT）与依西美坦（E）的比值推断。CYP2D6 多态性很常见，可影响 CYP2D6 蛋白活性和 E 水平。一些回顾性研究表明，E<16 nM 可能与预后不良有关。
在接受他莫昔芬治疗的 161 例患者的试验队列中，将目标 NDMT/E 比值定义为与 E 水平为 15 nM 相关，将他们分为“正常”（NM）和“慢代谢”（SM）CYP2D6 代谢组。然后在 52 例验证队列中测试该比值。根据标准方法（超快/广泛、中间或不良代谢者；UM/EM、IM、PM）或基于是否存在任何变异等位基因（V）与野生型（wt）的简化系统（wt/wt、wt/V、V/V）对患者进行表型分析。对源于胚系 DNA 的 CYP2D6 进行了全面的基因分型。
目标 NDMT/E 比值为 35 时，与 15 nM E 水平相关，将患者分为 NM（<35；N=117）和 SM（>35；N=44）组。该比值在验证队列中得到了独立验证。简化系统在预测无慢代谢患者方面表现更好，特异性和敏感性分别为 96%和 44%，而标准方法的敏感性为 81%，特异性为 83%。
与当前系统相比，基于是否存在任何变异的简化分类系统更能准确识别真正不是 CYP2D6 慢代谢者的患者。然而，由于 CYP2D6 基因型不是依西美坦水平的唯一决定因素，我们建议也应考虑直接测量依西美坦。
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