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.