Rapid Changes in Circulating Tumor Cells Following Anti-Angiogenic Therapy

Angiogenesis is essential for tumor growth and metastasis. Bevacizumab (Avastin™) is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Prior studies suggest that bevacizumab causes transient changes in tumor perfusion and oncostatic pressure. However, it has been difficult to directly demonstrate immediate effects in living patients. The high-definition circulating tumor cell (HD-CTC) assay allows for enumeration and cytologic analysis of CTCs without reliance on immunologic or physical separation methods. Here, we assess rapid changes in HD-CTCs immediately following bevacizumab administration in patients with metastatic castration resistant prostate cancer (CRPC). Peripheral blood was obtained in 8 subjects with CRPC before and within 2 h following bevacizumab. The median (range) of HD-CTCs observed immediately pre- and post- bevacizumab was 2.4 (0–352) and 40 (0–352) cells ml−1, respectively. Changes in apoptotic HD-CTCs were observed following bevacizumab in most patients. The HD-CTC assay can also be used to monitor androgen receptor (AR) expression, a therapeutic target particularly important for some prostate cancer treatments. As bevacizumab is not expected to directly interact with AR, we observed no change in the AR expression or sub-cellular localization in these patients. Following the bevacizumab administration, all subjects subsequently received docetaxel and everolimus along with bevacizumab over additional cycles in the context of a therapeutic clinical trial. Interestingly, the two subjects with the smallest variation in HD-CTCs following bevacizumab demonstrated the least response to subsequent treatment. These pilot data suggest CTC-based assays may be used to measure immediate effects associated with bevacizumab treatment at an individual patient level. Additional subjects and longer follow-up will be required to determine if immediate changes in HD-CTCs relate to therapeutic response and overall clinical outcome for patients with metastatic prostate cancer and other malignancies.