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Clinical Study
Circulating biomarkers of bevacizumab activity in patients with breast cancer
Neelima Denduluri, Sherry X. Yang, Arlene W. Berman, Diana Nguyen, David J. Liewehr, Seth M. Steinberg and Sandra M. Swain
volume 7 | issue 1
January 2008Pages: 15 - 20
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Purpose: 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. Experimental Design: 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.