A physiologic imaging pilot study of breast cancer treated with AZD2171.
BACKGROUND
This pilot study combined physiologic imaging, microcomputed tomography, and histologic tumor evaluation with a xenograft model of breast cancer to identify surrogates likely to correlate with response to AZD2171, an inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinases.


METHODS
MCF-7 cells transfected with vector (MCF-7neo) or VEGF (MCF(VEGF)) were implanted in the right and left mammary fat pads of 75 athymic mice. Treatment with AZD2171 (5 mg/kg/d) or vehicle control was initiated once tumors were established. Positron emission tomography with [11C]carbon monoxide to measure blood volume, [18F]fluoromethane to measure perfusion, and [18F]fluorodeoxyglucose to measure glucose utilization was done at baseline, and after 24 hours, 72 hours, and 4 weeks of treatment. After imaging, tumors were analyzed for microvessel density, proliferation, and VEGF expression.


RESULTS
AZD2171 induced significant inhibition of tumor growth in established MCF-7(neo) xenografts and regression of established MCF-7(VEGF) xenografts. An acute decrease in blood flow was detected in MCF-7(VEGF) tumors at 24 hours (P = 0.05). Tumor blood volume was increased in the MCF-7(VEGF) tumors but correlated with tumor size; blood volume did not change with AZD2171 therapy. Glucose utilization correlated with tumor size and did not change with acute or chronic AZD2171 therapy. Unlike blood flow and blood volume, glucose utilization was similar in MCF-7neo and MCF-7(VEGF) tumors. Microvessel density and proliferation acutely decreased in MCF-7(VEGF) tumors but returned to baseline during chronic therapy.


CONCLUSIONS
[18F]Fluoromethane imaging may be a useful surrogate for biological activity of AZD2171 with changes identified within 24 hours of starting therapy.
Miller
Kathy D
KD
Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA. kathmill@iupui.edu
Miller
Michael
M
Mehrotra
Sanjana
S
Agarwal
Beamon
B
Mock
Bruce H
BH
Zheng
Qi-Huang
QH
Badve
Sunil
S
Hutchins
Gary D
GD
Sledge
George W
GW
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000627:therapeutic use*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
D020533:Angiogenesis Inhibitors; D005462:Fluorine Radioisotopes; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C500926:cediranib; D007211:Indoles