Department of Surgery and Oncology, Section of Medical Oncology, Università di Palermo, Palermo, Italy.
Oncology. 2009;77 Suppl 1:57-68. doi: 10.1159/000258497. Epub 2010 Feb 2.
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with metastatic colorectal carcinoma. Among patients not carrying activating mutations in the KRAS gene, only a limited number will experience tumor response to these therapeutic agents. The role of BRAF mutations in determining resistance to this treatment is emerging through preclinical and clinical studies. Standardization and validation of laboratory mutation analysis is needed to allow an optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Clinical single-arm and randomized studies were conducted both in first-line and refractory settings to evaluate the correlation of KRAS mutational status and efficacy of cetuximab and panitumumab. The main trials on first-line regiments are CRYSTAL, which is looking at FOLFIRI (folinic acid, fluorouracil, irinotecan) + cetuximab, and OPUS, which is evaluating FOLFOX (folinic acid, fluorouracil, oxaliplatin) + cetuximab. The results of these trials have induced the European Medicines Agency to apply restrictions to its approval of cetuximab and panitumumab for use in metastatic colorectal cancer patients with wild-type KRAS tumors. However, the absence of KRAS mutations is not sufficient to assure clinical response to cetuximab and panitumumab. We need to discover further molecular biomarkers of impairment in this or other signaling pathways to identify responders more specifically. Preclinical rationale is available for combined therapies, which simultaneously target EGFR and the RAS/RAF/MAPK signaling pathways for metastatic colorectal cancer.
针对表皮生长因子受体 (EGFR) 的单克隆抗体改善了转移性结直肠癌患者的预后。在未携带 KRAS 基因激活突变的患者中，只有少数患者会对这些治疗药物产生肿瘤反应。通过临床前和临床研究，BRAF 突变在确定对这种治疗的耐药性方面的作用正在显现。需要对实验室突变分析进行标准化和验证，以允许在结直肠癌的管理中优化使用抗 EGFR 治疗。在一线和难治性环境中进行了临床单臂和随机研究，以评估 KRAS 突变状态与西妥昔单抗和帕尼单抗疗效的相关性。CRYSTAL 研究观察 FOLFIRI（亚叶酸钙、氟尿嘧啶、伊立替康）+西妥昔单抗，OPUS 研究评估 FOLFOX（亚叶酸钙、氟尿嘧啶、奥沙利铂）+西妥昔单抗，这两项是关于一线治疗方案的主要试验。这些试验的结果促使欧洲药品管理局对西妥昔单抗和帕尼单抗在转移性结直肠癌野生型 KRAS 肿瘤患者中的批准应用施加限制。然而，KRAS 突变缺失并不足以保证对西妥昔单抗和帕尼单抗的临床反应。我们需要发现其他信号通路中 EGFR 失活的进一步分子生物标志物，以更准确地识别应答者。针对转移性结直肠癌，同时针对 EGFR 和 RAS/RAF/MAPK 信号通路的联合治疗具有临床前理论依据。
