Lim Hyeong-Seok, Ju Lee Han, Seok Lee Keun, Sook Lee Eun, Jang In-Jin, Ro Jungsil
Research Institute and Hospital, National Cancer Center, Madu1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
J Clin Oncol. 2007 Sep 1;25(25):3837-45. doi: 10.1200/JCO.2007.11.4850.
The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer.
Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes.
Patients carrying CYP2D6*10/10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D610/10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D610/*10 than for others (5.0 v 21.8 months, P = .0032)
CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.
细胞色素P450 3A（CYP3A）和细胞色素P450 2D6（CYP2D6）酶在将他莫昔芬转化为其活性代谢产物的过程中起主要作用。CYP3A是一种高度可诱导的酶，主要受孕烷X受体（PXR）调控。本研究评估了CYP2D6和PXR基因多态性与他莫昔芬药代动力学（PK）及乳腺癌患者临床结局之间的关联。
测定他莫昔芬及其代谢产物的血浆浓度。在202例接受每日20 mg他莫昔芬治疗超过8周的患者中鉴定CYP2D6和PXR的常见等位基因。对202例患者中的12例以及另外9例接受他莫昔芬治疗的转移性乳腺癌患者评估与基因型相关的临床结局。
携带CYP2D6*10/10（n = 49）的患者4-羟基-N-去甲基他莫昔芬和4-羟基他莫昔芬的稳态血浆浓度显著低于其他基因型患者（n = 153；4-羟基-N-去甲基他莫昔芬：7.9对18.9 ng/mL，P <.0001；4-羟基他莫昔芬：1.5对2.6 ng/mL，P <.0001），而未发现PXR基因型之间存在差异。CYP2D610/10在转移性乳腺癌无反应者中显著更常见（100%对50%，P = 0.0186）。在Cox比例风险分析中，CYP2D6基因型和疾病部位数量是影响疾病进展时间（TTP）的显著因素。携带CYP2D610/*10的他莫昔芬治疗患者的中位TTP短于其他患者（5.0对21.8个月，P = 0.0032）。
CYP2D6*10/*10与活性他莫昔芬代谢产物的较低稳态血浆浓度相关，这可能会影响他莫昔芬对亚洲乳腺癌患者的临床结局。
