Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study.
3531 Background: Bevacizumab (B) in combination with chemotherapy prolongs progression-free survival (PFS) in patients with mCRC. However, the subgroup that derives greatest benefit with B is not known. Since B only targets VEGF A and given the redundancy within biologic family members, we hypothesized that overexpression of other VEGF ligands could constitute a mechanism of resistance. We tested this hypothesis using tumor samples from patients in the MAX study. METHODS: We analyzed tumor samples from 268 of 471 patients (56.9%) who were randomly assigned to capecitabine (C), or C and B (CB), or C, B, and mitomycin (CBM). We examined expression of VEGF A, B, C, D, R1 and R2 by immunohistochemistry using tissue microarrays. We assessed whether expression of these biomarkers (grade 0,1 vs 2 vs 3) was predictive for B for PFS and overall survival (OS) using interactions between biomarker expression and treatment. RESULTS: When each biomarker was examined singly, lower expression of VEGF D was associated with greater B benefits on PFS and OS (Table) and was the only significant factor biomarker in a step-down multivariate analysis for PFS. When examined singly, lower expression of VEGFR1 was associated with greater B benefits for OS (p=0.001 for treatment-biomarker interaction) but not PFS. VEGFR1 was the remaining significant biomarker in a step-down multivariate analysis for OS. CONCLUSIONS: High expression of VEGF D is predictive of resistance to B, particularly in terms of PFS. This finding is biologically plausible but requires confirmation in other trials. Selection of patients with mCRC for B treatment based on VEGF D expression may have the potential to increase absolute benefits and improve cost-effectiveness. [Table: see text].