Early changes in angiogenesis and hypoxia following bevacizumab therapy in primary breast cancer.

Abstract

1066 Background: Bevacizumab (BV), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), is an approved anti-angiogenic agent, but despite its widespread use, little is known about how tumours develop resistance to BV. We have conducted a window-of-opportunity study in which BV is administered as a short-term first-line treatment for primary breast cancer (PBC) patients, and assessed histological markers of tumour angiogenesis and hypoxia before and after therapy. Methods: 47 patients with locally advanced breast cancer were prospectively enrolled. Informed consent was obtained from all patients. A single infusion of BV (15 mg/kg) was given 2 weeks before starting neoadjuvant chemotherapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and core biopsies for immunohistochemistry (IHC) analysis were performed immediately prior to and 2 weeks after BV. 36 patients with invasive ductal carcinoma and good quality MRI scans and core biopsies were included in this analysis. Wilcoxon rank test and Spearman’s correlation test were used for statistical analysis. Results: IHC revealed a significant upregulation of carbonic anhydrase 9 (P = 0.04) and hypoxia inducible factor-1a (P = 0.001) following BV therapy along with a significant reduction in plasmalemma vesicle associated protein (PLVAP) (p=0.01) and Ki67 (p= 0.006). DCE-MRI analysis revealed a significant reduction in vessel permeability and blood flow following BV, as measured by a decrease in the forward transfer constant Ktrans (P < 0.0001) and the reverse rate constant kep (P < 0.0001). In addition, we found a significant negative correlation between CA9 levels and median Ktrans at baseline (Spearman’s rho = -0.46; P = 0.01). Conclusions: Using combined DCE-MRI and IHC analysis, we found that PBC patients treated with single-agent BV showed a decrease in markers of tumour angiogenesis, together with a corresponding increase in tumour hypoxia. Our results suggest that tumour hypoxia may be a key mechanism governing the early onset of resistance to BV therapy, and argue for the use of suitable combination therapies to overcome the resistance and ultimately improve patient survival.