There was no difference in ICAM-1 levels pre-treatment or after C2. Determine 2D – Overall, there was a decrease in E-selectin levels with treatment. more so with DB (P = 0.069). ICAM increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels F2R of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI demonstrated a greater fall in tumor perfusion calculated by IAUC90 in DB (P = 0.024). DCE-MRI also exhibited an overall decrease in tumor volume (P=0.012). Conclusion Bevacizumab plus docetaxel caused a greater increase in VEGF and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin. INTRODUCTION Numerous studies have exhibited that therapeutic disruption of nascent vasculature is effective in mediating tumor regression (1). A primary target for anti-angiogenic therapy is usually vascular endothelial growth factor (VEGF), a potent and specific regulator of tumor angiogenesis and endothelial cell survival (2-8). VEGF also induces vascular permeability, which is a critical step in promoting tumor growth, and induces the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) on endothelial cells (9-11). VCAM-1 is usually a type-1 transmembrane glycoprotein important for cell adhesion needed for metastasis and is expressed on endothelial cells in response to VEGF stimulation or inflammation (12). VCAM-1 is also present in a soluble form and may function as attractants for endothelial cells (13). Similar to VCAM-1, ICAM-1 is usually a member of the immunoglobulin-like adhesion molecules and high circulating levels have RU-SKI 43 been associated with a greater propensity for metastatic dissemination (14, 15). E-selectin is usually expressed on endothelial membranes as well as secreted, is usually upregulated by inflammation, and is associated with the development of metastasis (16). In addition, fluctuations in E-selectin levels may be a more specific marker RU-SKI 43 of breast cancer than other malignancies (17). Expression of these endothelial adhesion molecules appear to correspond with clinical disease status, and thus can be investigated as a surrogate marker for disease response [18, 19]. Bevacizumab (rhuMAbVEGF, Avastin; Genentech, San Francisco, CA) is usually a humanized monoclonal antibody with binding specificity for VEGF. Clinical trials investigating the effect of this antibody with or without chemotherapy in the treatment of locally-advanced or metastatic breast cancer have been RU-SKI 43 reported with modest clinical results (20-24). This supports the need to document the direct biologic consequence of bevacizumab therapy on breast cancer in order to differentiate its effects from that of chemotherapy. Wedam, et. al., examined tumor biopsy specimens in 21 patients with inflammatory and locally advanced breast cancer treated with bevacizumab (22). An analysis of breast cancer tissue sampled pre- and post-therapy revealed a median decrease of 66.7% in phosphorylated VEGFR2 (P = .004) and a median increase of 128.9% in tumor apoptosis (P = .0008). There were no significant changes in microvessel density (MVD) or VEGF-A expression. DCE-MRI, parameters reflected significantly reduced tumor blood perfusion following bevacizumab administration. A single-arm study of combination bevacizumab and docetaxel in metastatic breast cancer revealed a significant association between the cell adhesion molecule, E-selectin, and clinical response (23). There is evidence to RU-SKI 43 suggest that docetaxel administered on a weekly basis has potent anti-angiogenic effects in addition to its cytotoxic anti-tumor activity (25, 26). These anti-angiogenic effects of docetaxel increase synergistically with the addition of bevacizumab (27). These findings raise the question of the added benefit of bevacizumab to the anti-angiogenic effects of docetaxel in the treatment of breast cancer. In an attempt to target tumor vasculature and differentiate the anti-angiogenic behavior of chemotherapy from that of a targeted anti-angiogenesis inhibitor, we designed a phase II randomized trial of weekly docetaxel versus weekly docetaxel combined with bevacizumab in patients with inoperable breast cancer. We hypothesized that this patients receiving combination therapy with docetaxel and bevacizumab would experience a greater effect on angiogenesis exhibited by a greater reduction in tumor microvascular density, more significant alterations in circulating markers of endothelial adhesion, and a larger decrease in tumor perfusion as measured by DCE MRI than those receiving docetaxel alone. PATIENTS AND METHODS Patients Men and women 18 years old were eligible if they had newly-diagnosed, histologically-confirmed, inoperable adenocarcinoma of the breast as confirmed by consensus.