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Changes in HER2 Expression in Breast Cancer Xenografts After Therapy Can Be Quantified Using PET and ¹⁸F-Labeled Affibody Molecules

¹ National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and ² National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland

Correspondence: For correspondence or reprints contact: Jacek Capala, 10 Center Dr., Bldg. 10, Room 1B-37A, Bethesda, MD 20892. E-mail: capalaj{at}mail.nih.gov

In vivo imaging of human epidermal growth factor receptor type 2 (HER2) expression may allow direct assessment of HER2 status in tumor tissue and provide a means to quantify changes in receptor expression after HER2-targeted therapies. This work describes the in vivo characterization of the HER2-specific N-2-(4-¹⁸F-fluorobenzamido)ethyl]maleimide (¹⁸F-FBEM)–Z_HER2:342 Affibody molecule and its application to study the effect of 17 (dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on HER2 expression by PET. Methods: To assess the correlation of signal observed by PET with receptor expression, we administered the tracer to athymic nude mice bearing subcutaneous human breast cancer xenografts with different levels of HER2 expression. To study the downregulation of HER2, we treated the mice with 4 doses (40 mg/kg) of 17-DMAG, an inhibitor of heat-shock protein 90, known to decrease HER2 expression. The animals were scanned before and after treatment. After the last scan, the mice were euthanized and tumors were frozen for receptor analysis. Results: The tracer was eliminated quickly from the blood and normal tissues, providing high tumor-to-blood and tumor-to-muscle ratios as early as 20 min after injection. The high-contrast images between normal and tumor tissue were recorded for BT474 and MCF7/clone18 tumors. Low but still detectable uptake was observed for MCF7 tumors, and none for MDA-MB-468. The signal correlated with the receptor expression as assessed by immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay. The levels of HER2 expression estimated by post-treatment PET decreased 71% (P < 4 x 10^–6) and 33% (P < 0.002), respectively, for mice bearing BT474 and MCF7/clone18 tumors. These changes were confirmed by the biodistribution studies, enzyme-linked immunosorbent assay, and Western blot. Conclusion: Our results suggest that the described ¹⁸F-FBEM–Z_HER2:342 Affibody molecule can be used to assess HER2 expression in vivo by PET and monitor possible changes of receptor expression in response to therapeutic interventions.

Key Words: Affibody molecule • molecular imaging • HER2 • breast cancer • PET

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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