Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer.
Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer.
复制标题
DOI：
10.1093/jnci/djp280
复制
发表时间：
2009-10-07
期刊：
影响因子：
--
通讯作者：
Bardelli A
中科院分区：
文献类型：
--
作者：
Siena S;Sartore-Bianchi A;Di Nicolantonio F;Balfour J;Bardelli A
靶向表皮生长因子受体（EGFR）的单克隆抗体帕尼单抗和西妥昔单抗扩大了转移性结直肠癌的治疗选择范围。这些药物作为EGFR表达化疗难治性肿瘤患者的单药治疗的初步评价产生了约10%的反应率。通过免疫染色检测阳性EGFR表达并不能可靠地预测EGFR靶向治疗的临床结果，这一认识导致了对替代预测生物标志物的深入研究。EGFR下游信号通路的致癌激活，如KRAS、BRAF或PIK 3CA癌基因突变或PTEN肿瘤抑制基因失活，是结直肠癌进展的关键。肿瘤KRAS突变可能存在于35%-45%的结直肠癌患者中，已成为帕尼单抗或西妥昔单抗治疗耐药的重要预测标志物。此外，在携带野生型KRAS的结直肠肿瘤中，BRAF或PIK 3CA突变或PTEN表达缺失可能与EGFR靶向单克隆抗体治疗的耐药性相关，尽管这些额外的生物标志物在纳入临床实践之前需要进一步验证。对EGFR靶向单克隆抗体敏感性或耐药性的分子基础的额外了解将允许开发新的治疗算法，以确定最有可能对治疗有反应的患者，并且还可以为联合治疗以克服原发性耐药性提供理论依据。使用KRAS突变作为抗EGFR单克隆抗体（例如帕尼单抗或西妥昔单抗）治疗的选择生物标志物是转移性结直肠癌患者个体化治疗的第一个主要步骤。
The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. 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 mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS 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 KRAS, 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 KRAS 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.
登录
查看更多内容
影响因子：
8.8
作者：
Bianco, R.;Garofalo, S.;Rosa, R.;Damiano, V.;Gelardi, T.;Daniele, G.;Marciano, R.;Ciardiello, F.;Tortora, G.
通讯作者：
Tortora, G.
影响因子：
50.5
作者：
De Roock, W.;Piessevaux, H.;Tejpar, S.
通讯作者：
Tejpar, S.
影响因子：
45.3
作者：
Bibeau, Frederic;Lopez-Crapez, Evelyne;Boissiere-Michot, Florence
通讯作者：
Boissiere-Michot, Florence
影响因子：
45.3
作者：
Allegra, Carmen J.;Jessup, J. Milburn;Schilsky, Richard L.
通讯作者：
Schilsky, Richard L.
影响因子：
11.5
作者：
Ciardiello, F;Bianco, R;Tortora, G
通讯作者：
Tortora, G