EGFR单抗治疗晚期结直肠癌的疗效预测标志物的研究进展

Biomarkers predicting clinical response to EGFR-targeted monoclonal antibody therapy in patients with metastatic colorectal cancer

靶向EGFR的单克隆抗体西妥昔单抗和帕尼单抗的问世大大拓宽了转移性结直肠肿瘤疗效,而当人们意识到使用免疫组织化学技术检测EGFR蛋白表达阳性与应用EGFR单抗治疗的疗效并没有相关性,便致力于可能的疗效预测标志物的研究.EGFR信号转导系统下游的例如K-ras、BRAF、PIK3CA的基因突变,以及肿瘤抑制基因PTEN的失活都成了研究的热点.在结直肠癌中,K-ras基因突变率为35%-45%,已成为EGFR单克隆抗体治疗转移性结直肠癌的主要疗效预测标志物.另外,在K-ras野生型基因的患者中,BRAF、PIK3CA基因突变以及PTEN的缺失表达,都可能与EGFR单克隆抗体的耐药有关,但在这些可能的疗效预测标志物被运用到临床实践中前,还需进一步地研究以明确他们的价值,以期在选择适合接受EGFR单克隆抗体的患者中起到更大的作用.而K-ras基因突变被作为治疗前的疗效预测标志物,则是开创了转移性结直肠癌个体化治疗的第一步.

The emergence of monoclonal antibodies targeting the epidermal growth factor receptor（EGFR）,such as panitumumab and cetuximab,has expanded the range of treatment options for metastatic colorectal cancer.The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers.Oncogenic activation of signaling pathways downstream of the EGFR,such as K-ras,BRAF or PIK3CA mutations,or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer.Tumor K-ras mutations,which may be present in 35%-45% of patients with colorectal cancer,have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment.In addition,among colorectal tumors carrying wild-type K-ras,mutation of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment,although these additional biomarkers require further validation before incorporation into clinical practice.Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance.The use of K-ras mutations as a selection biomarker for anti-EGFR monoclonal antibody（eg,panitumumab or cetuximab） treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer.