Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis.


METHODS
Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m(2)) and docetaxel (75 mg/m(2)) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7.


RESULTS
A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone.


CONCLUSIONS
Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.
Wedam
Suparna Bonthala
SB
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 8901 Wisconsin Avenue, Building 8, Rm 5101, Bethesda, MD 20889-5015, USA.
Low
Jennifer A
JA
Yang
Sherry X
SX
Chow
Catherine K
CK
Choyke
Peter
P
Danforth
David
D
Hewitt
Stephen M
SM
Berman
Arlene
A
Steinberg
Seth M
SM
Liewehr
David J
DJ
Plehn
Jonathan
J
Doshi
Arpi
A
Thomasson
Dave
D
McCarthy
Nicole
N
Koeppen
Hartmut
H
Sherman
Mark
M
Zujewski
JoAnne
J
Camphausen
Kevin
K
Chen
Helen
H
Swain
Sandra M
SM
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D002199:Capillary Permeability; D005260:Female; D006801:Humans; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2