Investigation of Pathways Regulating Early Antiangiogenic Response to Bevacizumab Given Prior to Neoadjuvant Breast Cancer Chemotherapy.

TPS176 Background: There are no proven biomarkers of efficacy of anti-vascular endothelial growth factor (VEGF) therapies. The vast majority of these drugs are investigated in patients with advanced cancers where multiple mechanisms of resistance are likely to have been developed. An alternative approach is to use these drugs as short-term first line treatments in combination with detailed pharmacodynamic assessments. We decided to investigate bevacizumab since it exhibits specific VEGF antagonism compared with other multi-kinase inhibitors. The aim of this study is to determine the mechanism of anti-angiogenic response and to identify the pathological characteristics of breast cancer patients most likely to be benefited from bevacizumab. Methods: This is a two-center, phase II, nonrandomized, open label, investigator-led study. This study obtained ethical approval in June 2008. A total of 40 previously untreated breast cancer patients will be enrolled consecutively. Eligibility criteria are: women who are scheduled to commence neoadjuvant chemotherapy, with age ≥18 years, performance status 0-1, who have histology proven locally advanced breast cancer (LABC), with adequate bone marrow, renal and liver functions. Patients receive a single infusion of bevacizumab (15 mg/ kg) 2-3 weeks prior to their neoadjuvant chemotherapy. Pharmacodynamic assessments include Dynamic Contrast-Enhanced (DCE), Diffusion Weighted (DW) and Blood Oxygen Level Dependent (BOLD) MRI scans, core biopsies for gene array (Affymetrix Human Exon 1.0 ST) and immunohistochemistry analysis of VEGF pathways, blood samples for proteomics, circulating endothelial cells, circulating cytokines, microparticles, plasma tumour DNA and endothelial RNA markers. Each assay is performed at baseline and 2-3 weeks following bevacizumab. The primary endpoint of the study is to correlate baseline gene expression with MRI response after one dose of bevacizumab measured at two weeks to assess whether particular patterns of gene expression relate to changes in vascular volume and permeability, as measured by MRI. The study is ongoing and has recruited 31 patients to date. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Cancer Research UK, Roche