Recently, a VEGF assay that is preferential for small VEGF isoforms was reported to predict for benefit from bevacizumab in metastatic breast, pancreatic, and gastric cancers. However these results were of only borderline statistical significance and this assay was not predictive of benefit in colorectal, non-small cell lung, or renal cell cancers. The reason for these differences is not yet known, but may relate to differences

in biology or in differences in sample handling across these trials (95). Biomarker analyses from other phase III trial with bevacizumab have plasma VEGF-D, SDF1, and Ang2 in DNA Methyltransferase animal study pancreatic cancer and tumor tissue VEGFD measured by IHC in colorectal cancer (12,96). Inhibitors,research,lifescience,medical Phase III trials with pazopanib and bevacizumab have implicated high IL6 levels as a predictor of benefit from

these agents in renal cell Inhibitors,research,lifescience,medical cancer (97). Intriguingly, anti-angiogenic VEGFA isoforms have been described, although this field remains controversial (98). VEGFxxxb Inhibitors,research,lifescience,medical isoforms have anti-angiogenic properties and bind to bevacizumab; bevacizumab binding to these isoforms would theoretically deplete both bevacizumab and the anti-angiogenic VEGFxxxb ligands. Conversely low levels of VEGFxxxb would be predicted to describe a more VEGFA dependent and bevacizumab sensitive state. Interestingly, in an analysis of a subset of patients with tumor available from the 2nd line E3200 study (FOLFOX +/- bevacizumab) low ratios of VEGF165b:VEGFtotal measured

in tissue samples of mCRC patients correlated Inhibitors,research,lifescience,medical with clinical benefit from addition of bevacizumab compared to chemotherapy alone; and no benefit from bevacizumab was seen when the VEGF165b:VEGFtotal ratio was elevated (99). Genetic polymorphisms in VEGFA and VEGFR1 may influence angiogenic potential involving the tumor vasculature and response to anti-angiogenic therapies. Accordingly, multiple studies have investigated VEGF genotypes and clinical outcomes. Schneider Inhibitors,research,lifescience,medical et al. reported that the VEGF-2578 AA Cediranib (AZD2171) genotype was associated with both an overall survival benefit and less toxicity in the phase III E2100 trial of paclitaxel with or without bevacizumab in metastatic breast cancer (100). Furthermore, certain single nucleotide polymorphisms (SNPs) correlated with clinical outcomes in the AViTA and AVOREN trails, using bevacizumab in patients with metastatic pancreatic cancer and metastatic RCC, respectively. VEGFR1 SNP rs9582036 was associated with progression free survival in both trials, and overall survival for patients AC and CC genotypes. No genetic interaction was seen in placebo groups (93). Circulating endothelial cells and tumor vessel imaging with dynamic contrast-enhanced magnetic resonance imaging are also other emerging areas of biomarker research (93,101,102).