Wegman Pia, Elingarami Sauli, Carstensen John, Stål Olle, Nordenskjöld Bo, Wingren Sten
Department of Biomedicine and Surgery, Division of Cell Biology, Faculty of Health Sciences, Linköping University, 581 85 Linköping, Sweden.
Breast Cancer Res. 2007;9(1):R7. doi: 10.1186/bcr1640.
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 CYP2D64. 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 CYP3A53-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 CYP3A53 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.
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其生存期。尽管大多数患者从他莫昔芬治疗中获益，但许多乳腺肿瘤要么无反应，要么产生耐药性。由于他莫昔芬通过多态性酶广泛代谢，一种提出的耐药潜在机制是代谢改变。在本研究中，我们调查了细胞色素P450 3A5（CYP3A5 *3）、CYP2D6（*4）、磺基转移酶1A1（SULT1A1；*2）和尿苷二磷酸葡萄糖醛酸基转移酶2B15（UGT2B15；*2）功能多态性在接受他莫昔芬治疗的乳腺癌患者中的预后和/或预测价值。
总共677例接受他莫昔芬治疗的绝经后乳腺癌患者，其中238例被随机分配接受2年或5年的他莫昔芬治疗，采用聚合酶链反应（PCR）-限制性片段长度多态性或PCR-变性高效液相色谱法进行基因分型。
在总体人群中进行的预后评估显示，CYP2D64纯合子患者的无病生存期显著更好。对于CYP3A5、SULT1A1和UGT2B15，未观察到预后意义。在随机分组的患者中，我们发现，对于CYP3A5，3等位基因的纯合携带者在接受他莫昔芬2年治疗时复发风险倾向于增加，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）。在随机分配接受5年他莫昔芬治疗的组中，CYP3A53纯合子患者的生存模式转向无复发生存期（RFS）显著改善（HR = 0.20，95%CI = 0.07至0.55，P = 0.002）。在治疗持续时间与CYP2D6、SULT1A1或UGT2B15的基因型之间未发现可靠差异。在多变量Cox模型中也观察到，CYP3A53纯合子患者延长他莫昔芬治疗后RFS显著改善（HR = 0.13，CI = 0.02至0.86，P = 0.03），而对于CYP2D6、SULT1A1和UGT2B15则未发现差异。
他莫昔芬的代谢很复杂，耐药机制不太可能由单一多态性解释；相反，它是多种机制的组合。然而，目前的数据表明，CYP3A5基因变异可能预测他莫昔芬治疗的反应。
