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

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.

Keywords: angiogenesis inhibitors; breast neoplasms; fractals; magnetic resonance imaging; neoadjuvant therapy; pharmacokinetics.

Figure 1

Relative change in MRI-derived tumor volumes after 1, 12, and 25 weeks for the two treatment groups.

Figure 2

Probability density plots of time-to-peak (TTP) and area under the contrast curve (AUC) for individual breast tumor voxels during treatment with neoadjuvant chemotherapy-only (n = 32) or chemotherapy + bevacizumab (n = 38).

Figure 3

Relative change in time-to-peak (TTP) and area under the contrast curve (AUC) after 1, 12, and 25 weeks for breast cancer patients who received neoadjuvant treatment with chemotherapy-only or chemotherapy + bevacizumab. All changes are normalized to individual pretreatment values.

Figure 4

Probability density plots of $K^{trans}$, $k_{ep}$, $v_e$ and $v_p$ from the extended Tofts model for individual breast tumor voxels during treatment with neoadjuvant chemotherapy-only (control, n = 32) or neoadjuvant chemotherapy + bevacizumab (bevacizumab, n = 38).

Figure 5

Relative change in $K^{trans}$, $k_{ep}$, $v_e$, and $v_p$ after 1, 12, and 25 weeks for the breast cancer patients who received neoadjuvant treatment with chemotherapy (controls, n = 32) or chemotherapy + bevacizumab (bevacizumab, n = 38). All changes are normalized to individual pretreatment values.

Figure 6

Patient treated with bevacizumab showing intermediate pre-treatment fractal dimension (top), with a significant increase in fractal dimensionality after one week of treatment (bottom). The fractal dimension maps are shown to the right as colored overlays on T2-weighted images. To the left are the subtraction images that the fractal dimension is calculated from.

Figure 7

Patient treated with bevacizumab, showing high pretreatment fractal dimension (top), with a significant reduction after one week of treatment (bottom). Fractal dimension maps are shown to the right, and subtraction images are shown to the left.

Figure 8

Relative change in the fractal dimensionality of the subtraction images in the breast cancer patients who received neoadjuvant treatment with chemotherapy (controls, n = 32) or chemotherapy + bevacizumab (bevacizumab, n = 38).