Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer

Background: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. Methods: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. Results: Patients with low expression of VEGF-D (0, 1+) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CB+CBM), 0.21; 95% CI, 0.08-0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13-0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2+ PFS HR, 0.67; 95% CI, 0.45-1.00; OS HR, 0.82; 95% CI, 0.52-1.30; VEGF-D 3+ PFS HR, 0.77; 95% CI, 0.50-1.17; OS HR, 1.28; 95% CI, 0.79-2.09) (P interaction <0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. Conclusions: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.