Activating KRAS Mutations and Overexpression of Epidermal Growth Factor Receptor as Independent Predictors in Metastatic Colorectal Cancer Patients Treated With Cetuximab
Activating KRAS Mutations and Overexpression of Epidermal Growth Factor Receptor as Independent Predictors in Metastatic Colorectal Cancer Patients Treated With Cetuximab
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DOI：
10.1097/sla.0b013e3181bc9d96
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发表时间：
2010-02-01
影响因子：
9
通讯作者：
Wang, Jaw-Yuan
中科院分区：
文献类型：
--
作者：
Yen, Li-Chen;Uen, Yih-Huei;Wang, Jaw-Yuan
目的：西妥昔单抗（Cetuximab）是一种靶向表皮生长因子受体（EGER）的单克隆抗体，已被证明对转移性结直肠癌（mCRC）有效；然而，治疗反应是可变的，迫切需要预测反应的标志物。本研究旨在确定KRAS突变状态和EGFR表达在西妥昔单抗联合化疗的mCRC患者中的预测价值。背景数据：egfr靶向抗体的临床获益似乎仅限于mCRC患者的一个特定亚组。因此，在引入靶向化疗之前，确定可靠的mCRC患者预测因素至关重要。方法：95例接受西妥昔单抗联合FOLF1RI或FOLFOX-4化疗的mCRC患者纳入本研究。分别采用直接测序、免疫组化（IHC）和逆转录聚合酶链反应（RT-PCR）分析KRAS突变状态和EGFR表达水平。评估临床反应、无进展生存期（PFS）和总生存期（OS）以及KRAS突变状态/EGFR表达水平之间的关系。结果：在95例mCRC患者中，41例发现KRAS突变，78例观察到EGFR过表达（蛋白或mRNA水平）。在41个KRAS突变的肿瘤中，33个在密码子12、13、15或18处发现了激活突变，8个在密码子20、30和31处发现了非激活突变。55例患者对西妥昔单抗联合化疗有反应，49例为EGFR过表达，46例为野生型KRAS肿瘤状态。表达高EGFR水平或携带野生型KRAS的患者在西妥昔单抗联合化疗时更有可能获得更好的PFS和OS（均P < 0.05）。此外，肿瘤中未激活KRAS突变体的患者的PFS和OS明显优于激活KRAS突变体的患者（P < 0.05）。然而，对于野生型KRAS肿瘤状态的患者，EGFR表达仍然是临床反应的相关预测因子。结论：本研究提示，在西妥昔单抗联合化疗的mCRC患者中，激活KRAS突变体是一个特别重要的独立预测标志物，其中将激活KRAS突变体与EGER结合可以帮助识别最有可能对西妥昔单抗联合化疗有反应的患者亚组。
Objective: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGER), has been proven to be efficient in metastatic colorectal cancer (mCRC); however, the therapeutic response is variable and markers predictive of response are urgently required. This study was conducted to determinate the predictive values of KRAS mutation status and EGFR expression in mCRC patients treated with cetuximab plus chemotherapy.Summary Background Data: Clinical benefit with EGFR-targeting antibodies seems to be restricted to a particular subgroup of mCRC patients. Therefore, the identification of reliable predictive factors for mCRC patients is imperative before the introduction of targeted chemotherapy.Methods: Ninety-five mCRC patients receiving cetuximab plus the FOLF1RI or FOLFOX-4 chemotherapy were enrolled into the present study. KRAS mutation status/EGFR expression levels were analyzed using direct sequencing, immunohistochemistry (IHC), and reverse transcription-polymerase chain reaction (RT-PCR) assay, respectively. The association between clinical response, progression-free survival (PFS) and overall survival (OS) as well as KRAS mutation status/EGFR expression levels were evaluated.Results: Of 95 mCRC patients, KRAS mutations were identified in 41 cases, and EGFR overexpression (protein or mRNA levels) were observed in 78 patients. Among 41 tumors with KRAS mutation, 33 were found to be activating mutants at codons 12, 13, 15 or 18, while 8 were nonactivating mutants at codons 20, 30, or 31. Fifty-five patients responded to cetuximab plus chemotherapy, 49 were EGFR overexpression and 46 were wild-type KRAS tumor status. Patients with turners that express high EGFR levels or harbor wild-type KRAS are more likely to have a better PFS and OS when treated with cetuximab plus chemotherapy (all P < 0.05). Furthermore, patients with nonactivating KRAS mutants in tumors had a significantly better PFS and OS than patients with activating KRAS mutants (both P < 0.05). However, for patients with wild-type KRAS tumor status, EGFR expression remains a relevant predictor of clinical response.Conclusions: The study suggests that activating KRAS mutants is a particularly important independent predictive marker in mCRC patients treated with cetuximab plus chemotherapy, of which combing activating KRAS mutants and EGER could help to identify the subgroup of patients who are most likely to respond to cetuximab plus chemotherapy.