Journal of Nuclear Medicine Vol. 50 No. 11 1848-1856
© 2009 by Society of Nuclear Medicine
doi: 10.2967/jnumed.109.067231
Basic Science Investigation
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18F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice
Kristin McLarty1, Aisha Fasih1, Deborah A. Scollard1, Susan J. Done2,3, Douglass C. Vines4,5, David E. Green4, Danny L. Costantini1 and Raymond M. Reilly1,6,7
1 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada; 2 Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 3 Ontario Cancer Institute and Department of Pathology, University Health Network, Toronto, Ontario, Canada; 4 Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Hospital, Toronto, Ontario, Canada; 5 Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; 6 Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and 7 Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
Correspondence: For correspondence or reprints contact: Raymond M. Reilly, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON, Canada M5S 3M2. E-mail: raymond.reilly@utoronto.ca
Breast cancers (BCs) with high human epidermal growth factor
receptor type 2 (
HER2) expression are most likely to respond
to trastuzumab; however, the mechanisms of action of trastuzumab
are complex and there are no established biomarkers to accurately
monitor treatment outcome in individual patients. Therefore,
our aim was to determine, in human BC xenografts in athymic
mice treated with trastuzumab, whether there were any changes
in
18F-FDG uptake that were associated with response to the
drug and that could have utility in monitoring response in patients.
Methods: Baseline tumor uptake of
18F-FDG was measured in mice
with MDA-MB-361
HER2-overexpressing xenografts and MDA-MB-231
xenografts with low
HER2 expression by small-animal PET imaging
on day 0. Mice were treated with phosphate-buffered saline (PBS)
or trastuzumab (4 mg/kg), and small-animal PET was repeated
2 d after treatment. Maintenance doses of trastuzumab (2 mg/kg)
or PBS were administered on days 7 and 14, and mice were imaged
again on days 9 and 16. Tumor uptake was measured as percentage
injected dose per gram (%ID/g) by volume-of-interest analysis
on days 0 (baseline), 2, 9, and 16, followed by biodistribution
studies on day 16. Tumor growth was measured, and a tumor growth
index was calculated.
Results: The treatment of mice with trastuzumab,
compared with control mice treated with PBS, resulted in a significant
decrease in tumor uptake of
18F-FDG in
HER2-overexpressing MDA-MB-361
xenografts after 16 d of treatment (2.6 ± 0.8 %ID/g vs.
4.6 ± 1.8 %ID/g, respectively;
P < 0.03) but not after
2 or 9 d of treatment (
P = 0.28–0.32). In contrast, there
was no significant change in the tumor uptake of MDA-MB-231
xenografts with low
HER2 expression during the entire course
of therapy (4.4 ± 1.7 %ID/g vs. 3.6 ± 1.1 %ID/g,
respectively;
P = 0.31). Trastuzumab treatment, compared with
PBS treatment of controls, resulted in significant growth inhibition
of MDA-MB-361 xenografts as early as 10 d from the initiation
of treatment (tumor growth index, 0.7 ± 0.2 vs. 1.7 ±
0.3, respectively;
P < 0.0005), whereas no tumor growth inhibition
was observed for MDA-MB-231 xenografts (5.3 ± 2.7 and
5.2 ± 3.0;
P = 0.95).
Conclusion: Changes in the tumor
uptake of
18F-FDG after therapy accurately identified responding
and nonresponding human BC xenografts in athymic mice treated
with trastuzumab; however, diminished glucose utilization did
not precede changes in tumor volume.
Key Words: HER2 • trastuzumab •
18F-FDG • PET • tumor response
COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.
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