Inflammatory breast cancer (IBC) is a clinically and pathologically distinct form of locally advanced breast cancer associated with a rapid growth rate and high metastatic potential. IBC is highly angiogenic and the biology of this form of breast cancer is poorly understood. We have investigated microvessel density (MVD)estrogen receptor (ER) status, MIB-1 labeling index, p53, and c-erbB-2 by immunohistochemistry in archival specimens from 67 women diagnosed with breast cancer with or without the inflammatory phenotype in Tunisia to define intratumoral MVD and potential biologic markers that correlate with inflammatory breast cancer (IBC). In this study, we have found a significantly increased MVD in IBC as compared to non-IBC and confirmed IBC as being a highly vascular disease experimentally (for the first time). This finding supports anti-angiogenesis therapy as a strategy to treat patients with IBC. To extend this finding and to study the underlying mechanisms of the increased MVD (the regulation of tumor angiogenesis) in IBC, we'll study other angiogenesis-related protein markers Flt-1, KDR and Tie-2. In our study (MVD and biologic markers in IBC) we have found lower ER expression in IBC than in non-IBC, and observed a trend related to the loss of ER to the increased vascularization in IBC. Although the later did not reach the statistical significance (due to a relative small number of cases available), it raises a very interesting aspect of research in breast cancer. A recent experimental report has found that ER overexpression is associated with decreased tumor vascularization by down-regulating angiogenesis-related genes like VEGF and v 3. To extend our observation from this study, we'll continue to study ER and its role in suppression of tumor angiogenesis in IBC or in breast cancer in patient core biopsies taken from pre- and post-therapies from the anti-VEGF trial and in breast tissue specimens from the tissue microarray setting. We are performing a trial in inflammatory breast cancer patients with bevacizumab, anti-VEGF, and combination chemotherapy with biologic endpoints of changes in endothelial cell proliferation and apoptosis, dynamic MRI, and tissue VEGF levels. This is a pilot study in patients with previously untreated Stage IIIB/IV inflammatory breast cancer to evaluate angiogenesis parameters after treatment with rhuMAb VEGF - recombinant humanized monoclonal antibody vascular endothelial growth factor (bevacizumab). Inflammatory breast cancer (IBC) is an aggressive tumor associated with a poor prognosis. It is highly angiogenic and studies on tumor samples confirm increased microvessel density and the expression of VEGF thus providing an ideal disease for treatment with anti-angiogenesis therapy. In this study, we are evaluating molecular endpoints in patient tumor biopsies to assess for antiangiogenic activity of bevacizumab. We are also examining a functional endpoint, vascular permeability changes, using dynamic contrast-enhanced MRI of the breast. The first cycle of treatment will consist of bevacizumab alone followed by six cycles of bevacizumab in combination with doxorubicin and docetaxel (AT). Loco-regional therapy will follow and bevacizumab will be recommenced for eight cycles. Changes in endothelial cell proliferation, endothelial cell apoptosis and tissue VEGF will be assessed at baseline, three weeks after bevacizumab and after three cycles of AT/bevacizumab. Dynamic MRI is used to obtain kep, the redistribution constant, related to vascular permeability. To determine the variability of the values of the three molecular primary angiogenesis parameters, multiple biopsies will be sampled at the same time points. An attempt will be made to correlate each of the four primary angiogenesis parameters with time to progression/recurrence. This study is the first to combine doxorubicin chemotherapy with bevacizumab in untreated breast cancer patients. Evaluation of antiangiogenesis treatment in patients without prior chemotherapy will provide new information about the efficacy and biological mechanisms of bevacizumab. In addition, the opportunity to describe the vascular components of inflammatory breast cancer and its response to antiangiogenesis therapy will be important to advancing treatment options for this disease. There are now 14 patients on study. The establishment of an inflammatory breast cancer (IBC) registry and biospecimen repository is a project, spearheaded by Dr. Paul H. Levine, the George Washington University Medical Center. This project, funded by a grant from the Department of Defense awarded to Paul H. Levine (PHL), includes developing a national registry of volunteers with IBC. Subjects will provide access to medical records, pathology records, slides, blocks and tissue (fixed and frozen) and x-rays and consent to an interview. The goal is to recruit approximately 300 volunteers, at least 18 years of age or older. We will obtain paraffin blocks or unstained slides from each case and frozen tissue when possible. Mark E. Sherman, DCEG, NCI, acting as the main study pathologist, will review slides and pathology reports. He will record standardized features describing the histopathologic characteristics of the tumors and may review immunostains or othr slide based assays performed as part of this project. We plan to study biological markers that have been associated with inflammatory breast cancer to help in classification of these tumors. These include estrogen receptor (ER), progesterone receptor (PR), p53, c-erB-2, microvessel density (MVD), E-cadherin, and RhoCGTPase. Given the highly angiogenic nature of inflammatory breast cancer, we would also like to evaluate angiogenesis parameters that may be useful in targeting therapy. These include hypoxia-inducible factor 1 alpha HIF-1 (HIF-1 alpha), VEGF-A protein expression, VEGF-receptor 3 (also known as flt-4), and VEGFR2 (also known as KDR). These molecular markers also will be assessed in our ongoing IBC trial described previously.
| Thukral, Arpi; Thomasson, David M; Chow, Catherine K et al. (2007) Inflammatory breast cancer: dynamic contrast-enhanced MR in patients receiving bevacizumab--initial experience. Radiology 244:727-35 |
| Wedam, Suparna Bonthala; Low, Jennifer A; Yang, Sherry X et al. (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24:769-77 |
