KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer
KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer
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DOI：
10.1158/0008-5472.can-06-0191
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Laurent-Puig, P
中科院分区：
文献类型：
--
作者：
Lièvre, A;Bachet, JB;Laurent-Puig, P
抗表皮生长因子受体（抗EGFR）西妥昔单抗已被证明是有效的转移性结直肠癌。对这种药物的临床反应的分子机制仍然未知。参与EGFR相关信号通路的细胞内效应物的遗传改变可能对这种靶向治疗的反应产生影响。在这项研究中，30例接受西妥昔单抗治疗的转移性结直肠癌患者的肿瘤通过直接测序筛查KRAS、BPW和PIK 3CA突变，并通过显色原位杂交筛查EGFR拷贝数。30例患者中有11例（37%）对西妥昔单抗有反应。在13例肿瘤（43%）中发现KRAS突变，与西妥昔单抗无应答显著相关（11例应答患者中0%的KRAS突变与19例无应答患者中68.4%的KRAS突变; P = 0.0003）。肿瘤中无KRAS突变的患者的总生存期显著高于肿瘤突变的患者（P = 0.016;中位数，16.3 vs 6.9个月）。在3例患者（10%）中发现EGFR拷贝数增加，与西妥昔单抗的客观肿瘤缓解显著相关（P = 0.04）。总之，在这项研究中，KRAS突变是西妥昔单抗治疗耐药的预测因子，并与预后不良相关。EGFR扩增不像最初报告的那样频繁，也与对这种治疗的反应有关。
The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BPW, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.