Noninvasive 89 Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18 F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

The current standard for breast PET imaging is ¹⁸ F-FDG. The heterogeneity of ¹⁸ F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. ¹⁸ F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm ³ MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with ⁸⁹ Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that ⁸⁹ Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of ¹⁸ F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, ⁸⁹ Zr-transferrin and ¹⁸ F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA-MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5-1 μM). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Results: Head-to-head comparison showed that ⁸⁹ Zr-transferrin targets TNBC tumors significantly better ( P < 0.05-0.001) than ¹⁸ F-FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA ( P < 0.01-0.001 for responding cell lines), compared with vehicle treatment. MYC and TfR protein expression, along with receptor-mediated internalization of transferrin, was also significantly decreased upon drug treatment in MDA-MB-231 and MDA-MB-157 cells ( P < 0.01-0.001). Conclusion: ⁸⁹ Zr-transferrin targets human TNBC primary tumors significantly better than ¹⁸ F-FDG, as shown through PET imaging and biodistribution studies. ⁸⁹ Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC.
(© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)