Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Ann Surg. 2010 Feb;251(2):254-60. doi: 10.1097/SLA.0b013e3181bc9d96.
Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), 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.
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.
Ninety-five mCRC patients receiving cetuximab plus the FOLFIRI 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.
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 tumors 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.
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 EGFR could help to identify the subgroup of patients who are most likely to respond to cetuximab plus chemotherapy.
表皮生长因子受体（EGFR）单克隆抗体西妥昔单抗已被证明对转移性结直肠癌（mCRC）有效；然而，治疗反应存在差异，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 表达在接受西妥昔单抗联合化疗的 mCRC 患者中的预测价值。
针对 EGFR 的抗体的临床获益似乎仅限于 mCRC 患者的特定亚组。因此，在引入靶向化疗之前，确定 mCRC 患者的可靠预测因素至关重要。
本研究共纳入 95 例接受西妥昔单抗联合 FOLFIRI 或 FOLFOX-4 化疗的 mCRC 患者。分别采用直接测序、免疫组织化学（IHC）和逆转录聚合酶链反应（RT-PCR）检测 KRAS 突变状态/EGFR 表达水平。评估临床反应、无进展生存期（PFS）和总生存期（OS）与 KRAS 突变状态/EGFR 表达水平之间的关系。
在 95 例 mCRC 患者中，41 例存在 KRAS 突变，78 例存在 EGFR 过表达（蛋白或 mRNA 水平）。在 41 例 KRAS 突变肿瘤中，33 例为密码子 12、13、15 或 18 的激活突变，8 例为密码子 20、30 或 31 的非激活突变。55 例患者对西妥昔单抗联合化疗有反应，49 例 EGFR 过表达，46 例 KRAS 肿瘤状态野生型。肿瘤 EGFR 高表达或 KRAS 野生型的患者接受西妥昔单抗联合化疗时 PFS 和 OS 更优（均 P<0.05）。此外，肿瘤中存在非激活 KRAS 突变的患者 PFS 和 OS 明显优于激活 KRAS 突变的患者（均 P<0.05）。然而，对于 KRAS 肿瘤状态野生型的患者，EGFR 表达仍然是临床反应的一个相关预测因素。
该研究表明，激活的 KRAS 突变是接受西妥昔单抗联合化疗的 mCRC 患者的一个特别重要的独立预测标志物，结合激活的 KRAS 突变和 EGFR 有助于识别最有可能对西妥昔单抗联合化疗有反应的患者亚组。
