MRI Assessment of Changes in Tumor Vascularization during Neoadjuvant Anti-Angiogenic Treatment in Locally Advanced Breast Cancer Patients

SIMPLE SUMMARY: Experimental and clinical studies have revealed that vascular endothelial growth factor (VEGF) is the predominant angiogenic factor in breast cancer. VEGF expression correlates with inferior outcomes and advanced-stage breast cancer. Bevacizumab is a humanized anti-VEGF monoclonal antibody and has been shown to improve response rates in the treatment of breast cancer, but has failed to improve progression-free survival or overall survival. Anti-VEGF treatment can temporarily normalize tumor vascularization and it is hypothesized that there might be a window of opportunity for chemotherapy. Dynamic contrast-enhanced MRI (DCE-MRI) is the most accurate radiological tool to aid in staging and treatment monitoring of advanced breast cancer. In this work, we showed that DCE-MRI is a sensitive tool to measure the treatment effect of bevacizumab and that it shuts down the vascularization early and abruptly. DCE-MRI may be a suitable tool to find an eventual therapeutic window, and possibly identify a subgroup that would benefit the most from anti-VEGF treatment. ABSTRACT: Anti-VEGF (vascular endothelial growth factor) treatment improves response rates, but not progression-free or overall survival in advanced breast cancer. It has been suggested that subgroups of patients may benefit from this treatment; however, the effects of adding anti-VEGF treatment to a standard chemotherapy regimen in breast cancer patients are not well studied. Understanding the effects of the anti-vascular treatment on tumor vasculature may provide a selection of patients that can benefit. The aim of this study was to study the vascular effect of bevacizumab using clinical dynamic contrast-enhanced MRI (DCE-MRI). A total of 70 women were randomized to receive either chemotherapy alone or chemotherapy with bevacizumab for 25 weeks. DCE-MRI was performed at baseline and at 12 and 25 weeks, and in addition 25 of 70 patients agreed to participate in an early MRI after one week. Voxel-wise pharmacokinetic analysis was performed using semi-quantitative methods and the extended Tofts model. Vascular architecture was assessed by calculating the fractal dimension of the contrast-enhanced images. Changes during treatment were compared with baseline and between the treatment groups. There was no significant difference in tumor volume at any point; however, DCE-MRI parameters revealed differences in vascular function and vessel architecture. Adding bevacizumab to chemotherapy led to a pronounced reduction in vascular DCE-MRI parameters, indicating decreased vascularity. At 12 and 25 weeks, the difference between the treatment groups is severely reduced.