Page 76 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Chapter 4
89Zr-labeled bevacizumab in breast cancer, lung cancer, renal cell carcinoma, neuroendocrine tumors and pontine glioma
Another target for treatment of breast cancer and many other tumor types is vascular endothelial growth factor A (VEGF-A), which is involved in tumor angiogenesis. Overexpression of VEGF-A has been reported in malignant breast tumors and ductal carcinoma in situ and has been related to aggressiveness of the disease. Bevacizumab is a mAb that targets all splice variants of VEGF-A, both small isoforms which can diffuse freely in the circulation, as well as larger isoforms which are primarily matrix-bound. Despite the fact that VEGF-A is not a membrane target like HER2, it is partly associated with the tumor blood vessels and to some extent with the extracellular matrix of tumor cells, which could enable imaging of tumor lesions.
It can be hypothesized that local VEGF-A concentration reflects whether tumor progression is driven by angiogenesis and if anti-angiogenic treatment is likely to be effective. Therefore, 89Zr-bevacizumab-PET is of interest for several applications: biological characterization of tumors, prediction of therapeutic outcome, and treatment evaluation of VEGF-A targeting drugs.
89Zr-labeled bevacizumab in breast cancer
Gaykema et al. performed a study to assess whether VEGF-A can be visualized by 89Zr-bevacizumab-PET in patients with primary breast cancer who were scheduled for surgery (26). In this study 37 MBq 89Zr-labeled bevacizumab (5 mg) was administered and PET scans were acquired at 4 days p.i.. The same dose was used in a previous study with 111Indium-labeled bevacizumab, which visualized all known melanoma lesions (27). Tumor uptake of 89Zr-bevacizumab was observed in 25 of 26 tumors in 23 patients with primary breast cancer. The false-negative tumor was a 10 mm VEGF-A-positive invasive ductal carcinoma. Besides assessment of tumor uptake in the primary tumors, uptake of 89Zr-bevacizumab in lymph node metastasis regions was evaluated. 4 of 10 metastasis-involved lymph node regions were detected in 9 patients. 0 of 4 axillary regions with lymph node metastases were detected by 89Zr-bevacizumab-PET.
For all available tumors (n=25) VEGF-A expression was quantified by enzyme-linked immunosorbent assay. 89Zr-bevacizumab uptake in tumors correlated with the VEGF-A tumor levels measured. Microvessel density on immunohistochemistry was not correlated with 89Zr-bevacizumab uptake. This was the first clinical study showing a significant correlation between antigen
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