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A physiologic imaging pilot study of breast cancer treated with AZD2171
Kathy D Miller1, Michael Miller, Sanjana Mehrotra
1Division of Hematology and Oncology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA. kathmill@iupui.edu
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.
Experimental Design:
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.
Insights
[18F]Fluoromethane imaging may predict response to AZD2171, a VEGF receptor inhibitor, in breast cancer xenografts. Changes in tumor perfusion were observed within 24 hours of treatment initiation.
Area of Science:
- Oncology
- Radiology
- Pharmacology
Background:
- This pilot study investigated potential imaging biomarkers for AZD2171 (VEGF receptor tyrosine kinase inhibitor) efficacy in breast cancer.
- A xenograft model was used to combine physiologic imaging, microcomputed tomography, and histology.
Purpose of the Study:
- To identify imaging surrogates that correlate with response to AZD2171 treatment.
- To evaluate the early biological effects of AZD2171 on tumor physiology.
Main Methods:
- MCF-7 breast cancer cells (vector or VEGF transfected) were implanted in mice.
- Tumors were treated with AZD2171 or vehicle control.
- Positron emission tomography ([11C]CO, [18F]fluoromethane, [18F]fluorodeoxyglucose) was used to measure blood volume, perfusion, and glucose utilization.
- Tumor microvessel density, proliferation, and VEGF expression were analyzed post-imaging.
Main Results:
- AZD2171 inhibited tumor growth (MCF-7neo) and caused regression (MCF-7VEGF).
- [18F]Fluoromethane imaging detected an acute decrease in perfusion in MCF-7VEGF tumors within 24 hours.
- Blood volume and glucose utilization did not show significant changes with AZD2171 therapy and correlated with tumor size.
- Microvessel density and proliferation decreased acutely but returned to baseline with chronic therapy.
Conclusions:
- [18F]Fluoromethane imaging appears to be a promising surrogate for assessing the biological activity of AZD2171.
- Changes in tumor perfusion detected by [18F]fluoromethane imaging can indicate early treatment response within 24 hours.
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