Rolla R, Vidali M, Meola S, Pollarolo P, Fanello M R, Nicolotti C, Saggia C, Forti L, Agostino F D, Rossi V, Borra G, Stratica F, Alabiso O, Bellomo G
Departmentt of Medical Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
Clin Lab. 2012;58(11-12):1211-8.
The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects.
61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology.
A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005).
Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.
他莫昔芬是一种广泛用于治疗和预防雌激素受体阳性乳腺癌（ER+）患者复发的药物，其副作用已在临床试验中有所报道，但迄今为止，尚无关于这些副作用与细胞色素P450 2D6（CYP2D6）酶活性增加（超快代谢者，UMs）之间可能关联的信息。因此，本研究的目的是评估多个功能性CYP2D6等位基因的存在与副作用发生之间的关联。
对61例接受他莫昔芬单药治疗的ER+乳腺癌女性进行了调查，以评估CYP2D6超快代谢者（UM）表型与副作用之间的关系。使用一种新的DNA微阵列技术对16种CYP2D6多态性进行基因分型。
超快代谢者（UM；高活性）中对他莫昔芬有两种或更多药物不良反应的患者数量（7/9；77.8%）与广泛代谢者（EM；正常活性）、中间代谢者（IM；活性降低）和慢代谢者（PM；无活性）中至少有两种副作用的患者数量（19/52，36.5%）之间存在高度显著差异（差异为41.2%，95%置信区间6 - 61%，Fisher精确检验，p = 0.030）。在比较两组（UM与EM-IM-PM）的副作用数量时也观察到了类似差异（中位数和四分位间距，IQR：AM/EM/IM为1，IQR 0 - 2 vs. ULTRA为2，IQR 2 - 4；Mann-Whitney p = 0.005）。
我们的结果表明CYP2D6基因重复与他莫昔芬副作用之间存在新的关联，表明CYP2D6在副作用发生中可能起作用。
