The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab

Abstract

Shu-Dong Zhang,1,2,* Cian M McCrudden,3,* Chen Meng,4 Yao Lin,4 Hang Fai Kwok1,31Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau, Special Administrative Region of the People’s Republic of China; 2Center for Cancer Research and Cell Biology, Queen’s University Belfast, United Kingdom; 3School of Pharmacy, Queen’s University Belfast, United Kingdom; 4College of Life Sciences, Fujian Normal University, Fujian, People’s Republic of China*These authors contributed equally to this workAbstract: 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.Keywords: colon cancer, VEGFA, FLT1, KDR, angiogenesis, survival