Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer
Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer
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DOI：
10.1007/s10549-013-2565-3
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发表时间：
2013-06-01
影响因子：
3.8
通讯作者：
Regierer, Anne C.
中科院分区：
文献类型：
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作者：
Karle, Jennifer;Bolbrinker, Juliane;Regierer, Anne C.
CYP2D6基因型对他莫昔芬（Tam）在早期乳腺癌中疗效的影响已被广泛分析，结果相互矛盾。然而，关于这种对晚期乳腺癌（ABC）的潜在影响的数据很少。我们假设，Tam在具有功能性CYP2D6等位基因的患者中比在CYP2D6活性受损的患者中更有效。既往或正在接受姑息性Tam治疗（20 mg/d）的ABC患者符合条件。从血液（n = 51）和福尔马林固定的石蜡包埋组织（n = 43）中提取基因组DNA。测定血液中的CYP2D6 * 2、* 3、* 4、* 5、* 6、* 10、* 17、* 29、* 41、CYP2D6重复和倍增以及组织样本中的CYP2D6 * 4。主要终点是无进展生存期（PFS）;次要终点包括临床获益（CB）和总生存期（OS）。回顾性分析了有关生存率和治疗效果的临床图表。基因分型是盲法进行的，临床数据单独分析。确定了94例患者，中位年龄为59岁（29 - 90岁）。在6例患者中，基因分型未显示结论性结果，因此这些患者被排除在进一步分析之外。基因分型结果如下：1.1%超快速型，84.1%广泛型，3.4%中间型和11.4%弱代谢型。与至少具有一个功能性等位基因（EM/EM、EM/IM、EM/PM）的患者相比，不具有任何完全功能性等位基因（IM/IM、IM/PM、PM/PM）的患者的PFS和OS显著更短（PFS：p = 0.017; HR = 2.19; 95% CI 1.15 - 4.18; OS：p = 0.028; HR = 2.79; 95% CI 1.12 - 6.99）。EM组的CB率为73%，IM + PM组为38.5%（p = 0.019）。我们的研究结果表明，CYP2D6基因型对Tam治疗ABC的疗效有显着影响。与辅助治疗相比，姑息治疗的证据是一致的。应考虑在ABC中进行CYP2D6检测。
The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.