However, 52 of these were in Arm C and thus were not included in the analysis. treated with FOLFOX4+bevacizumab compared to FOLFOX4 alone (median 8.0 months vs 5.2 months, p 0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio median (5.9 months vs 6.3 months). These findings held after adjustment for other clinical and demographic features. Overall survival (OS) was increased in Arm A (median 13.6 months) compared with Arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF165b:VEGFtotal group between FOLFOX+bevacizumab (10.8 months) and FOLFOX alone (11.3months). CONCLUSION Low VEGF165b:VEGFtotal ratio may be a predictive marker for Tenalisib (RP6530) bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit. Introduction Bevacizumab, a recombinant humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF), has become a standard Tenalisib (RP6530) component of the treatment of patients with metastatic colorectal cancer. In 2004 a landmark study comparing bolus irinotecan, 5 fluorouracil and leucovorin (IFL) and placebo treatment with IFL and bevacizumab(1) showed a 4.7 and 4.2 month increase in median overall survival (OS) and progression free survival (PFS) respectively. In 2007 the ECOG E3200 trial of 829 patients with previously treated metastatic colorectal cancer exhibited that addition of bevacizumab to oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX4)(2) resulted in a 2.1 and 2.6 month increase in median overall and progression free survival respectively. There have as yet been no definitive studies identifying biomarkers that predict outcome to bevacizumab therapy. VEGF-A is usually a product of one gene encoding multiple isoforms, identified by their amino-acid number, and c-terminal sequence. Alternative splicing of exon 8 results in two families of proteins(3). Proximal splice site (PSS) usage generates a short open reading frame (ORF) of six amino-acids common to the pro-angiogenic VEGF isoforms. An alternative distal splice site (DSS) in exon 8 results in a different six amino-acid ORF, resulting in proteins of the same length as the pro-angiogenic isoforms, but with a different c-terminal sequence. These isoforms that are antiangiogenic in physiological systems(4), in experimental VEGF-driven angiogenesis(5) and in pathological angiogenesis driven by VEGF(6, 7), including in tumors(5, 8C12). These isoforms, the most common of which is usually VEGF165b form a substantial portion of total VEGF in many tissues, including normal colon (12). VEGF165b is usually relatively down-regulated in colon cancer, but to a variable extent(12). VEGF165b binds bevacizumab with the same affinity as VEGF165(12), and over-expression of VEGF165b in human colon carcinomas produced in mice conferred resistance to bevacizumab treatment(12). These findings suggest that VEGF165b may interfere with bevacizumab treatment. This led us to propose that bevacizumab may be more effective against tumors in which VEGF165b levels are low. We sought to test this hypothesis in samples from patients treated with bevacizumab/FOLFOX in one of the original pivotal phase III clinical trials of bevacizumab/FOLFOX in colorectal carcinoma. Methods Patient Characteristics In the Rabbit Polyclonal to MSK1 clinical trial E3200, eligible patients were randomly assigned to receive FOLFOX4 in combination with bevacizumab (Arm A); FOLFOX4 without bevacizumab (Arm B); or bevacizumab alone (Arm C). Random assignment was stratified on the basis of prior radiation therapy and Eastern Cooperative Group (ECOG) performance status. The primary end point of the study was overall survival. Tenalisib (RP6530) A total of 829 patients were enrolled onto the study between November 2001 and April 2003 from 221 sites in the United States and South Africa. Nine patients who received treatment were determined to be ineligible, leaving 820 randomized patients analyzable. In February 2003, the bevacizumab-alone arm of the study was closed to accrual after interim analysis suggested inferior survival when compared with the chemotherapy-containing arms of the study. The final study sample sizes were therefore Arm A: 286 patients, Arm B: 291 patients, Arm C: 243 patients (see physique 1 for breakdown.