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Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The purpose of the study was to investigate the associations between uptake of 111In-DTPA-trastuzumab, tumour HER2 density and response to trastuzumab (Herceptin) of human breast cancer (BC) xenografts in athymic mice.

Materials and methods

The tumour uptake of 111In-DTPA-trastuzumab in athymic mice bearing BC xenografts with increasing HER2 density (0 to 3+) was evaluated. Specific uptake ratios were established in biodistribution (SUR) and imaging studies (ROI-SUR) using 111In-labeled mouse IgG (111In-DTPA-mIgG). Further corrections were made for circulating radioactivity using tumour-to-blood ratios defined as a localization index (LI) and region-of-interest localization index (ROI-LI), respectively. Mice were treated with trastuzumab (Herceptin). A tumour growth inhibition index (TGI) was calculated and relative TGIs calculated by dividing the TGI of control by that of trastuzumab-treated mice.

Results

Strong, nonlinear associations with HER2 density were obtained if the uptake of 111In-DTPA-trastuzumab was corrected for nonspecific IgG localization (i.e., SUR; r 2 = 0.99) and circulating radioactivity (i.e., LI; r 2 = 0.87), but without these corrections, the association between HER2 density and tumour uptake was poor (r 2 = 0.22). There was a strong association between ROI-SUR and ROI-LI values and HER2 expression (r 2 = 0.90 and r 2 = 0.95, respectively. All tumours were imaged. Relative TGI values were associated with increasing uncorrected tumour uptake of 111In-DTPA-trastuzumab but not always with HER2 density (i.e., MCF-HER2-18 cells with trastuzumab-resistance).

Conclusion

HER2 expression (0 to 3+) can be differentiated using 111In-DTPA-trastuzumab, but requires correction of tumour uptake for nonspecific IgG localization and circulating radioactivity. The uncorrected uptake of 111In-DTPA-trastuzumab was associated with tumour response to trastuzumab.

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Acknowledgments

This research was supported by grants from the Ontario Cancer Research Network (No. 03-NOV-0428) with funds from the Province of Ontario. K.M. is the recipient of the MDS Nordion Graduate and an Ontario Graduate Scholarship and is a Canadian Institutes of Health Research Strategic Training Fellow in the Excellence in Radiation Research for the 21st Century (EIRR21) Program. Parts of this research were presented at the Canadian Breast Cancer Research Alliance Reasons for Hope Conference, Montreal, PQ, May 6–8, 2006. The authors are grateful to Dr. Pieter Jager, McMaster University, for his review of the manuscript and helpful comments.

Conflict of Interest Statement

The authors have no known conflict of interest with submission of this manuscript for publication. Dr. Raymond Reilly has a Materials Transfer Agreement with Genentech, Inc. for a separate project. All sources of support relating to these studies have been acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada

    Kristin McLarty, Bart Cornelissen, Deborah A. Scollard & Raymond M. Reilly

  2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Susan J. Done

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Susan J. Done

  4. Department of Pathology, University Health Network, Toronto, ON, Canada

    Susan J. Done

  5. Genetics Program, North York General Hospital, Toronto, ON, Canada

    Kathy Chun

  6. Department of Medical Imaging, University of Toronto, Toronto, ON, Canada

    Raymond M. Reilly

  7. Toronto General Research Institute, University Health Network, Toronto, ON, Canada

    Raymond M. Reilly

  8. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada

    Raymond M. Reilly

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  1. Kristin McLarty
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Correspondence to Raymond M. Reilly.

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McLarty, K., Cornelissen, B., Scollard, D.A. et al. Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts. Eur J Nucl Med Mol Imaging 36, 81–93 (2009). https://doi.org/10.1007/s00259-008-0923-x

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