Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: current evidence and future perspectives

Angiogenesis is a universal requirement for the growth of solid tumours beyond the limits of oxygen diffusion from the existing vasculature. The expression and function of proangiogenic and antiangiogenic factors are altered in solid malignancies to drive net neoangiogenesis. Vascular endothelial growth factor (VEGF) has been confirmed in several clinical trials as an important therapeutic target in colorectal cancer (CRC) treatment. However, given that the efficacy of antiangiogenic agents appears to be limited to a subset of patients, the identification of who will obtain the greater benefit from this therapy or suffer from specific toxicities and when or for how long they should be administered in the treatment algorithm are major open questions for clinicians and challenges for present and future research. Current evidence indicates some predictive value for particular circulating measures, such as an increase in VEGF, a decrease in vascular endothelial growth factor receptor 2 (VEGFR-2) or circulating endothelial cells, tissue biomarkers, microvessel density, KRAS and BRAF gene mutations or polymorphisms affecting components of the VEGF pathway. Many questions relating to these and other surrogate biomarkers, however, remain unanswered and their clinical usefulness has yet to be proven. This review will focus on the present status of knowledge and future perspectives for developing molecular tools to foresee and monitor antiangiogenic therapy activity in CRC patients.