Zhang Shu-Dong, McCrudden Cian M, Meng Chen, Lin Yao, Kwok Hang Fai
Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau, Special Administrative Region of the People's Republic of China ; Center for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom.
School of Pharmacy, Queen's University Belfast, United Kingdom.
Onco Targets Ther. 2015 Apr 15;8:835-43. doi: 10.2147/OTT.S80518. eCollection 2015.
Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer. However, not all patients benefit from inhibition of VEGF. Ras status is a powerful biomarker for response to anti-epidermal growth factor receptor therapy; however, an appropriate biomarker for response to anti-VEGF therapy is yet to be identified. VEGF and its receptors, FLT1 and KDR, play a crucial role in colon cancer progression; individually, these factors have been shown to be prognostic in colon cancer; however, expression of none of these factors alone was predictive of tumor response to anti-VEGF therapy. In the present study, we analyzed the expression levels of VEGFA, FLT1, and KDR in two independent colon cancer datasets and found that high expression levels of all three factors afforded a very poor prognosis. The observation was further confirmed in another independent colon cancer dataset, wherein high levels of expression of this three-gene signature was predictive of poor prognosis in patients with proficient mismatch repair a wild-type KRas status, or mutant p53 status. Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients. Since bevacizumab has been proven to be an important drug in the treatment of advanced stage colon cancer, our results suggest that the three-gene signature approach is valuable in terms of its prognostic value, and that it should be further evaluated in a prospective clinical trial to investigate its predictive value to anti-VEGF treatment.
通过抑制血管内皮生长因子（VEGF）途径靶向血管生成已成功应用于晚期结直肠癌的治疗。然而，并非所有患者都能从VEGF抑制中获益。Ras状态是抗表皮生长因子受体治疗反应的有力生物标志物；然而，抗VEGF治疗反应的合适生物标志物尚未确定。VEGF及其受体FLT1和KDR在结肠癌进展中起关键作用；单独来看，这些因素已被证明在结肠癌中具有预后价值；然而，这些因素单独的表达均不能预测肿瘤对抗VEGF治疗的反应。在本研究中，我们分析了两个独立结肠癌数据集中VEGFA、FLT1和KDR的表达水平，发现所有这三个因素的高表达预示着非常差的预后。这一观察结果在另一个独立结肠癌数据集中得到进一步证实，其中这三个基因特征的高表达预示着错配修复功能正常、KRas野生型状态或p53突变状态患者的预后不良。最重要的是，在一组接受贝伐单抗治疗的患者中，这一特征还预测了肿瘤对靶向VEGFA的抗体贝伐单抗治疗的反应。由于贝伐单抗已被证明是晚期结肠癌治疗中的一种重要药物，我们的结果表明，三基因特征方法在预后价值方面具有重要意义，并且应该在前瞻性临床试验中进一步评估其对抗VEGF治疗的预测价值。
