Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer.
Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer.
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DOI：
10.1186/bcr1640
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Wingren S
中科院分区：
文献类型：
--
作者：
Wegman P;Elingarami S;Carstensen J;Stål O;Nordenskjöld B;Wingren S
他莫昔芬治疗可降低雌激素受体阳性乳腺癌患者的复发风险并延长生存期。即使大多数患者受益于他莫昔芬，许多乳腺肿瘤要么没有反应，要么变得耐药。由于他莫昔芬是广泛代谢的多态性酶，一个提出的机制，潜在的阻力是改变代谢。在本研究中，我们调查了细胞色素P450 3A 5 CYP 3A 5（*3）、CYP 2D 6（*4）、磺基转移酶1A 1（SULT 1A 1; *2）和UDP-葡萄糖醛酸基转移酶2B 15（UGT 2B 15; *2）的功能多态性在他莫昔芬治疗的乳腺癌患者中的预后和/或预测价值。在所有的，677他莫昔芬治疗绝经后乳腺癌患者，其中238人被随机分配到2或5年的他莫昔芬，基因型通过使用PCR与限制性片段长度多态性或PCR与变性高效液相色谱法。在总人群中进行的预后评估显示，CYP 2D 6 *4纯合子患者的无病生存期显著更好。对于CYP 3A 5、SULT 1A 1和UGT 2B 15，未观察到预后意义。在随机组中，我们发现CYP 3A 5 *3等位基因纯合子携带者在接受他莫昔芬治疗2年后复发风险增加，尽管这在统计学上不显著（风险比（HR）= 2.84，95%置信区间（CI）= 0.68至11.99，P = 0.15）。在随机接受5年他莫昔芬治疗的组中，CYP 3A 5 *3纯合子患者的无复发生存率（RFS）显著提高（HR = 0.20，95%CI = 0.07 - 0.55，P = 0.002）。在治疗持续时间和CYP 2D 6、SULT 1A 1或UGT 2B 15基因型之间未观察到可靠的差异。在多变量考克斯模型中也观察到，在CYP 3A 5 *3纯合子中延长他莫昔芬治疗的RFS显著改善（HR = 0.13，CI = 0.02 - 0.86，P = 0.03），而在CYP 2D 6、SULT 1A 1和UGT 2B 15中未观察到差异。他莫昔芬的代谢是复杂的，耐药的机制不太可能由单一的多态性来解释;相反，它是几种机制的组合。然而，目前的数据表明，CYP 3A 5的遗传变异可以预测对他莫昔芬治疗的反应。
Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer. In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography. The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15. The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.
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影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
通讯作者：
Schuetz, E
影响因子：
3.8
作者：
Nowell, SA;Ahn, JY;Ambrosone, CB
通讯作者：
Ambrosone, CB
影响因子：
3.9
作者：
Koch, I;Weil, R;Wojnowski, L
通讯作者：
Wojnowski, L
影响因子：
4.8
作者：
JORDAN, VC;HALDEMANN, B;ALLEN, KE
通讯作者：
ALLEN, KE
影响因子：
45.3
作者：
OSBORNE, CK;WIEBE, VJ;DEGREGORIO, MW
通讯作者：
DEGREGORIO, MW