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. Dr. Swain has 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, she has 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, she'll study other angiogenesis-related protein markers Flt-1, KDR and Tie-2. Also, these angiogenesis-related factors and the expression of VEGF-C and -D and of VEGFR-3 in regulation of lymphangiogenesis will be studied in a large study in patients with IBC in North America in collaboration with Dr. Paul Levine at the George Washington University. In her study (MVD and biologic markers in IBC) she has 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 her observation from this study, she'll continue to study ER and its role in suppression of tumor angiogenesis in IBC or in breast cancer. The expression of ER, VEGF and v 3 will be studied in a large setting of inflammatory breast cancer in collaboration with Dr. Cathy Schairer in the Division of Cancer Epidemiology and Genetics (Egyptian IBC Study) and in patient core biopsies taken from pre- and post-therapies from her anti-VEGF trial and in breast tissue specimens from the tissue microarray setting. Dr. Swain is 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. Since the group began seeing patients for this study in the fall of 2001, they have fielded 30 patient calls, with 21 patients evaluated at the clinical center and yielding seven patients enrolled on study. For this study, a total of twenty patients will be accrued. Neutropenia with one case of febrile neutropenia, diarrhea, and corticosteroid-associated hyperglycemia have been the only grade III and IV toxicities seen with this regimen and were expected with this chemotherapy combination.
| 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 |
