Association between VEGF Splice Isoforms and Progression-Free Survival in Metastatic Colorectal Cancer Patients Treated with Bevacizumab

Abstract

PURPOSE Bevacizumab improves survival for metastatic colorectal cancer patients with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF165b levels treated with bevacizumab. METHODS Blinded tumor samples from the phase-III trial of FOLFOX4±bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX+bevacizumab (Arm A) and 53 samples from patients treated with FOLFOX4 (Arm B), and PFS, and overall survival (OS) analysed based on PI relative to median ratio. RESULTS Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median 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 bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit.

CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients

“…2B). The ratio between splice variants has been shown to be functionally relevant, therefore we further analysed the ratio between expression levels of CXCR4-1 and CXCR4-2 in our samples [24]. The CXCR4-1/CXCR4-2 ratio was uniformly distributed in the cell line panel with two outliers; A673 cell line without CXCR4-1 expression and COH cell line with a high CXCR4-1/CXCR4-2 ratio (Table S1).…”

Compartment Model Predicts VEGF Secretion and Investigates the Effects of VEGF Trap in Tumor-Bearing Mice

“…For example, we assume the normal tissue is skeletal muscle, although other tissues and organs secrete and contain VEGF (51), but are not as well-characterized as muscle. We include two major VEGF isoforms (VEGF 120 /VEGF 121 and VEGF 164 /VEGF 165 ); however, other isoforms such as VEGF 188 /VEGF 189 (52) and VEGF xxxb (53, 54) also influence angiogenesis and may impact anti-VEGF therapies. Recent studies also show that other VEGF ligands and receptors contribute to angiogenesis (55–57), and the model can be expanded in the future to include these molecular species.…”

Translational Predictive Biomarker Analysis of the Phase 1b Sorafenib and Bevacizumab Study Expansion Cohort

“…They show that high pretreatment circulating concentrations of VEGF-A and low pretreatment circulating neuropilin-1 were prognostic for improved survival (HR 0.7) (31). A similar survival prognostic, but not predictive, value was observed for VEGF-A concentrations in a series of other studies of bevacizumab Ϯ chemotherapy in solid tumors (32,33). Angiome profiling was also done in a gemcitabine Ϯ bevacizumab-randomized trial (CALGB 80303) identifying a different survival prognostic signature in the bevacizumab versus placebo arms, both of which included IGFBP1 and PDGF-AA (34).…”