Circulating biomarkers of bevacizumab activity in patients with breast cancer.
OBJECTIVE
Noninvasive markers of anti-vascular endothelial growth factor (VEGF) therapy are needed. Soluble vascular cell adhesion molecule (sVCAM-1), soluble VEGF receptor-2 (sVEGFR-2), and plasma VEGF levels were assessed as potential biomarkers of therapy with bevacizumab. Tumor samples were evaluated for VEGFR-2 mutations before and after bevacizumab.


METHODS
Twenty-one patients with breast cancer underwent neoadjuvant treatment with bevacizumab for 1 cycle followed by 6 cycles of bevacizumab, chemotherapy, and filgrastim. Peripheral blood samples were collected at baseline, post cycles 1, 4 and 7. sVCAM-1, VEGF and sVEGFR-2 levels were measured by enzyme-linked immunosorbent assay (ELISA). Exons 17-26 of VEGFR-2 were sequenced on tissue samples from 20 patients at baseline and post cycle 1 to evaluate for tumor mutations.


RESULTS
From baseline to post cycle 1, sVCAM-1 and sVEGFR-2 values increased by a median of 180.5 ng/ml (p < 0.0001) and 1927 ng/ml respectively (p = 0.0003). Baseline VEGF, sVEGFR-2, and sVCAM-1 levels nor changes in sVEGFR-2 and sVCAM-1 levels were associated with clinical response. Median baseline sVEGFR-2 levels were 11322 ng/ml and 7524 ng/ml in patients with (n = 5) and without (n = 6) wound healing problems respectively, (p = 0.052). In 40 samples where tumor VEGFR-2 sequencing was obtained, no mutations were seen compared to the reference sequence.


CONCLUSIONS
sVCAM-1 and sVEGFR-2 values increased significantly after treatment with bevacizumab, possibly due to compensatory mechanisms secondary to VEGF inhibition. sVEGFR-2 levels were somewhat higher in patients with wound healing problems and may potentially predict patients at higher risk of this complication. There were no tumor VEGFR-2 mutations.
Breast Cancer Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Heath, Bethesda, Maryland, USA.
Neelima
N
Denduluri
Sherry X
SX
Yang
Arlene W
AW
Berman
Diana
D
Nguyen
David J
DJ
Liewehr
Seth M
SM
Steinberg
Sandra M
SM
Swain
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood* / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2