Circulating levels of anti-angiogenic VEGF-A isoform (VEGF-Axxxb) in colorectal cancer patients predicts tumour VEGF-A ratios.
OBJECTIVE
Bevacizumab as an adjunct to chemotherapy improves survival for some patients with metastatic colorectal cancer. Immunohistochemical staining of samples from the registration ECOG E3200 trial of bevacizumab with FOLFOX demonstrated that only patients with carcinomas expressing low levels of VEGF-A165b, an anti-angiogenic splice variant of the Vascular Endothelial Growth Factor family of proteins, benefited from bevacizumab treatment. To identify a more useful biomarker of response we tested the hypothesis that circulating VEGF-A165b levels correlate with immunohistochemical staining.


METHODS
17 patients with biopsy proven colorectal adenocarcinoma had pre-operative blood samples drawn. They underwent resection and had post-resection blood drawn. The plasma was analysed for levels of VEGF-Axxxb using enzyme-linked immunosorbent assay (ELISA) and the tumour blocks stained for VEGF-Axxxb and pan-VEGF-A. The normalised ratio of VEGF-Axxxb expression to that of panVEGF-A expression scored by IHC was calculated and correlated with plasma VEGF-A165b levels.


RESULTS
Plasma levels of VEGF-Axxxb significantly correlated with the VEGF-Axxxb:panVEGF-A ratio (r=0.594, P<0.02) in colorectal cancers. Median plasma VEGF-Axxxb levels were 151 pg/ml. The mean (1.5±0.17) and median, IQR (1.8, 1-2) IHC scores of the patients with greater than median plasma VEGF-Axxxb were significantly greater than those with less than median plasma VEGF-Axxxb levels (mean ± SEM=0.85±10.12, median, IQR=1, 0.54-1).


CONCLUSIONS
These results suggest that plasma VEGF-Axxxb levels could be an effective biomarker of response to Bevacizumab. These results indicate that a prospective trial is warranted to explore the use of plasma VEGF-Axxxb levels to stratify patients for colorectal cancer treatment by bevacizumab.
Department of Physiology and Pharmacology, Microvascular Research Laboratories, University of Bristol Bristol, United Kingdom.
John
J
Bunni
Department of Pathology, Bristol Royal Infirmary Bristol, United Kingdom.
Golda
G
Shelley-Fraser
Department of Pathology, Bristol Royal Infirmary Bristol, United Kingdom.
Kirsty
K
Stevenson
Department of Physiology and Pharmacology, Microvascular Research Laboratories, University of Bristol Bristol, United Kingdom.
Sebastian
S
Oltean
Department of Physiology and Pharmacology, Microvascular Research Laboratories, University of Bristol Bristol, United Kingdom.
Andy
A
Salmon
Department of Physiology and Pharmacology, Microvascular Research Laboratories, University of Bristol Bristol, United Kingdom.
Steven J
SJ
Harper
Department of Physiology and Pharmacology, Microvascular Research Laboratories, University of Bristol Bristol, United Kingdom.
James G
JG
Carter
Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Bristol, United Kingdom.
David O
DO
Bates
VEGF; VEGF165b; bevacizumab; colorectal cancer; splicing