Impact of FcγRIIa-FcγRIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan
Impact of FcγRIIa-FcγRIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan
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DOI：
10.1200/jco.2008.18.0463
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发表时间：
2009-03-01
影响因子：
45.3
通讯作者：
Boissiere-Michot, Florence
中科院分区：
文献类型：
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作者：
Bibeau, Frederic;Lopez-Crapez, Evelyne;Boissiere-Michot, Florence
目的抗表皮生长因子受体抗体西妥昔单抗对伊立替康难治性转移性结直肠癌（mCRC），主要是野生型KRAS肿瘤显示出活性。西妥昔单抗还可通过抗体依赖性细胞介导的细胞毒性（ADCC）发挥抗肿瘤作用，其中抗体Fc部分与免疫细胞表达的Fc受体（Fc γ R）相互作用。ADCC受Fc γ RIIa-H131 R和Fc γ RIIIa-V158 F多态性的影响，这两种多态性分别与利妥昔单抗和曲妥珠单抗治疗的滤泡性淋巴瘤和转移性乳腺癌具有临床相关性。我们研究了Fc γ R多态性和KRAS突变与伊立替康难治性结直肠癌患者治疗西妥昔单抗加irinotecan.Patients和MethodsTumor和69例患者的正常组织中的KRAS突变进行了筛选，使用敏感的多重检测和基因型的Fc γ RIIa和Fc γ RIIIa多态性直接测序和多重等位基因特异性聚合酶链反应，分别。结果与反应和无进展生存期（PFS）相关。结果KRAS突变与较低的反应率（4%对27%的非突变患者; P = 0.021）和较短的PFS（3.0对5.3个月; P = 0.021）。Fc γ RIIa-131 H/H和/或Fc γ IIIa-158 V/V基因型患者的PFS长于131 R和158 F携带者（5.5 vs 3.0个月; P = .005）。对于突变的KRAS患者，差异仍然显著。多因素分析显示，KRAS突变和Fc γ R联合状态是影响PFS的独立危险因素。结论Fc γ RIIa/Fc γ RIIIa多态性联合应用是西妥昔单抗联合伊立替康治疗mCRC患者疾病进展的预后因素。由于这些多态性在突变型KRAS mCRC中也具有临床相关性，因此推测ADCC在西妥昔单抗疗效中具有重要作用。J Clin Oncol 27：1122-1129. (C)2009年美国临床肿瘤学会
PurposeThe antiepidermal growth factor receptor antibody cetuximab shows activity in irinotecan-refractory metastatic colorectal cancer (mCRC), mainly in wild-type KRAS tumors. Cetuximab may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) in which antibody Fc portion interacts with Fc receptors (Fc gamma Rs) expressed by immune cells. ADCC is influenced by Fc gamma RIIa-H131R and Fc gamma RIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of Fc gamma R polymorphisms and KRAS mutation with the outcome of irinotecan-refractory mCRC patients treated with cetuximab plus irinotecan.Patients and MethodsTumor and normal tissues from 69 patients were screened for KRAS mutations using a sensitive multiplex assay and genotyped for Fc gamma RIIa and Fc gamma RIIIa polymorphisms by direct sequencing and multiplex allele-specific polymerase chain reaction, respectively. The results were correlated with response and progression-free survival (PFS).ResultsKRAS mutations were associated with lower response rate (4% v 27% in nonmutated patients; P = .021) and shorter PFS (3.0 v 5.3 months; P = .021). Patients with Fc gamma RIIa-131H/H and/or Fc gamma IIIa-158V/V genotypes had longer PFS than 131R and 158F carriers (5.5 v 3.0 months; P = .005). The difference remained significant for mutated-KRAS patients. By multivariate analysis, KRAS mutation and Fc gamma R combined status were independent risk factors for PFS.ConclusionCombined Fc gamma RIIa/Fc gamma RIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed. J Clin Oncol 27: 1122-1129. (C) 2009 by American Society of Clinical Oncology