Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab
Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab
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DOI：
10.1200/jco.2006.10.5437
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发表时间：
2007-08-01
影响因子：
45.3
通讯作者：
Mauro, David J.
中科院分区：
文献类型：
--
作者：
Khambata-Ford, Shirin;Garrett, Christopher R.;Mauro, David J.
抗表皮生长因子受体（EGFR）抗体西妥昔单抗对多种上皮性肿瘤显示出活性，然而，仅在一部分患者中观察到反应。进行这项研究，以确定与疾病控制与西妥昔单抗治疗的患者的标志物。患者和MethodsOne百十例转移性结直肠癌患者参加了西妥昔单抗单药治疗试验。对来自强制治疗前转移性活检的RNA进行转录谱分析，以识别其表达与最佳临床反应相关的基因。EGFR和K-ras基因突变分析和EGFR基因拷贝数分析进行预处理biopsies.ResultsGene表达谱的DNA显示，表达高水平的EGFR配体epiregulin和双调蛋白的肿瘤患者更有可能与西妥昔单抗（EREG，P = .000015; AREG，P = .000025）的疾病控制。此外，肿瘤不具有K-ras突变的患者比具有K-ras突变的患者具有显著更高的疾病控制率（P = .0003）。此外，EREG或AREG高表达的肿瘤患者的无进展生存期（PFS）也显著长于EREG或AREG低表达的患者（EREG：P = 0.0002，风险比[ HR] = 0.47，中位PFS分别为103.5 v57天; AREG：P <0.0001，HR = 0.44，中位PFS分别为115.5和57天）。结论：具有高基因表达水平的表皮调节蛋白和双调蛋白的肿瘤患者和具有野生型K-ras的患者更有可能在西妥昔单抗治疗后获得疾病控制。可以进一步开发确定的标志物，以选择西妥昔单抗治疗的患者。
PurposeThe antiepidermal growth factor receptor ( EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab.Patients and MethodsOne hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies.ResultsGene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab ( EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations ( P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival ( PFS) than patients with low expression ( EREG: P = .0002, hazard ratio [ HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively).ConclusionPatients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.