Heterogeneity in the angiogenic response of a BT474 human breast cancer to a novel vascular endothelial growth factor-receptor tyrosine kinase inhibitor: assessment by voxel analysis of dynamic contrast-enhanced MRI.
OBJECTIVE
To investigate the heterogeneity in the angiogenic response of a human breast cancer xenograft to a novel vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor, AG-013736, using dynamic contrast-enhanced MR imaging (DCE-MRI).


METHODS
Changes in pharmacokinetic parameters in a seven-day interval were compared between AG-treated and control groups, using Gd-DTPA and albumin-(Gd-DTPA)30. A voxel-by-voxel analysis was performed to produce parametric spatial pharmacokinetic parametric maps and histograms. Histogram segmentation was used to quantify the heterogeneity in tumor response to therapy, and compared with conventional descriptive measures of distribution in terms of their capacity to separate control from AG-treated tumors.


RESULTS
The albumin-(Gd-DTPA)30 endothelial transfer constant, Kps, showed changes with AG-013736 treatment and tumor growth. The changes were highly heterogeneous for individual segments of the histogram with different Kps values, and the overall patterns in which the frequency distribution changed differed significantly between the two groups. A change in the number of voxels with Kps ranging from 0.03 to 0.14 mL/min/(100 mL tissue) was the most sensitive variable for separating control from AG-treated tumors (P = 0.0008). Parametric maps of the kinetic parameters also showed spatial heterogeneity in tumor response to treatment. The Kps maps depicted rapid development of central necrosis as a result of AG-013736 treatment. Maps of v(p) demonstrated a marked increase at peripheral regions of necrotic areas. Similar trends were noted in the Gd-DTPA rate constant Ktrans distribution.


CONCLUSIONS
This study demonstrates the value of histogram analysis of maps of pharmacokinetic parameters for assessing heterogeneity in tumor response to antiangiogenic therapy. Changes in the number of voxels within certain segments of the Kps histogram were the most sensitive variable for separating control from AG-treated tumors.
Li
Ka-Loh
KL
Department of Radiology, University of California-San Francisco, San Francisco, California 94143-1290, USA.
Wilmes
Lisa J
LJ
Henry
Roland G
RG
Pallavicini
Maria G
MG
Park
John W
JW
Hu-Lowe
Dana D
DD
McShane
Teresa M
TM
Shalinsky
David R
DR
Fu
Y-J
YJ
Brasch
Robert C
RC
Hylton
Nola M
NM
D000818:Animals; D000077784:Axitinib; D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D007089:Image Enhancement; D007093:Imidazoles; D007191:Indazoles / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor