Selected 2003 and 2002 Inflammatory Breast Cancer published research.

More recent research (2003) is at the top of the page, 2002 research is further down the page.

Links to free full text (where available) will open in a new browser tab/window. If free full text is not available, copy the citation and check with the reference librarian at a local public or college library for assistance in obtaining a copy of the full article.

2003

Van Pelt, AE., et al. (2003). Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clinical Breast Cancer, 4(5), 348-53. Abstract below, free full text not available.

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.

Harris, EE., et al. (2003). Ten-year outcome after combined modality therapy for inflammatory breast cancer. International Journal of Radiation Oncology, Biology, Physics, 55(5), 1200-8. Abstract below, free full text not available.

PURPOSE: To evaluate the long-term outcome of combined modality therapy for inflammatory breast cancer. METHODS AND MATERIALS: The data from 54 women treated between 1983 and 1996 for inflammatory breast cancer were analyzed. Patients with metastatic disease or disease progression on induction chemotherapy were excluded. Induction chemotherapy was given to 52 patients. Mastectomy was performed in 52 patients. Radiotherapy was delivered to the breast or chest wall and regional lymph nodes in all patients. The median follow-up for all patients was 5.1 years. RESULTS: The 5- and 10-year overall survival rate was 56% and 35%, respectively; the corresponding relapse-free survival rates were 49% and 34%. Patients with a pathologic complete response after chemotherapy with or without preoperative radiotherapy had better 5- and 10-year overall survival rates (65% and 46%, respectively) and 5- and 10-year relapse-free survival rates (59% and 50%, respectively) compared with patients without a pathologic complete response. Those patients had a 5- and 10-year relapse-free survival rate of 45% and 27%, respectively. Locoregional failure at 5 and 10 years was 8% and 19%, respectively. CONCLUSION: The outcomes for patients completing multimodality therapy compare favorably with published data; however, the exclusion of patients with progression during induction chemotherapy may account in part for these results. The pathologic complete response rate was found to be an important prognostic factor. Selected patients with inflammatory breast cancer have the potential for long-term survival.

Giordano, SH., & Hortobágyi, GN. (2003). Inflammatory breast cancer: clinical progress and the main problems that must be addressed. Breast Cancer Research, 5(6), 284-8. Abstract below, free full text of article may be found at link above.

Inflammatory breast cancer is a rare but highly aggressive form of locally advanced breast cancer. Historically, this disease was uniformly fatal; however, with the advent of induction chemotherapy and carefully coordinated multimodality treatment, the prognosis of these patients has improved. This article reviews the clinical characteristics of inflammatory breast cancer and the recent advances in therapy.

Cristofanilli, M., Buzdar, AU., & Hortobágyi , GN. (2003). Update on the management of inflammatory breast cancer. The Oncologist, 8(2), 141-8. Abstract below, free full text of article may be found at link above.

Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast carcinoma, with the clinical and biological characteristics of a rapidly proliferating disease. The multidisciplinary management of IBC has changed in the past 3 decades and is presently clearly outlined in sequence, with preoperative or neoadjuvant chemotherapy representing the mainstay of treatment. Anthracyclines and taxanes are the most effective cytotoxic agents in the management of primary breast cancer and should be the standard of treatment for women with IBC. Locoregional treatment includes radiotherapy with or without surgery and continues to play a major role after appropriate medical treatment. The many investigations into the particular molecular determinants of IBC development have provided several interesting new therapeutic targets. Combination regimens that include angiogenic modulators, farnesyl transferase inhibitors, and p53 modulators hold great promise in the medical management of IBC. Future therapeutic approaches should focus on these discoveries so that we can improve the overall prognosis for women with IBC.

2002

Shirakawa, K. et al. (2002). Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft. Cancer Research, 62(2), 560-6. Abstract below, free full text of article may be found at link above.

In the present study, we examined hemodynamics in vasculogenic mimicry (VM) and angiogenesis of inflammatory breast cancer (IBC) xenografts (WIBC-9), having previously reported on the unique histological features and molecular basis of these processes (K. Shirakawa et al., Cancer Res., 61: 445-451, 2001). Histologically, the WIBC-9 xenografts exhibited invasive ductal carcinoma with a hypervascular structure (angiogenesis) in the tumor margin and VM without endothelial cells, central necrosis, or fibrosis in the tumor center. Results of molecular analysis indicated that WIBC-9 had a vasculogenic phenotype, including expression of Flt-1 and Tie-2. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-coursed dynamic micromagnetic resonance angiography analysis (with our newly developed intravascular macromolecular magnetic resonance imaging contrast agent), electromicroscopy, and immunohistochemistry, demonstrated blood flow and a VM-angiogenesis junction in the central area of the WIBC-9 tumor. It has previously been considered impossible to prove a connection between VM and angiogenesis using angiography,
because there are no intravascular macromolecular magnetic resonance imaging contrast agents that do not exhibit significant leakage through the vascular wall. In the present study, laser-captured microdissection was performed in regions of WIBC-9 tumors that exhibited VM without endothelial cells, central necrosis, or
fibrosis, revealing expression of human-Flt-1 and human-Tie2 and the absence of human-CD31, human-endothelin B receptor, and human-thrombin receptor. These facts led us to hypothesize that the VM of WIBC-9 involves hemodynamics that serve to feed WIBC-9 cells, and this in turn suggests a connection between VM and
angiogenesis.

Kobayashi, H. et al. (2002). Rapid accumulation and internalization of radiolabeled Herceptin in an inflammatory breast cancer xenograft with vasculogenic mimicry predicted by the contrast-enhanced dynamic mri with the macromolecular contrast agent G6-(1B4M-Gd)(256). Cancer Research, 62(3), 860-6. Abstract below, free full text of article may be found at link above.

The rapid blood flow and perfusion of macromolecules in the inflammatory breast cancer xenograft (WIBC-9), which exhibits a “vasculogenic mimicry” type of angiogenesis without the participation of endothelial cells and expresses high levels of the HER-2/neu antigen, was evaluated in mice using 3D-micro-MR angiography using a novel macromolecular MR contrast agent [G6-(1B4M-Gd)(256)]. Herceptin, which recognizes the HER-2/neu antigen and has similar size (10 nm) to G6-(1B4M-Gd)(256), accumulated and internalized in the WIBC-9 tumors more quickly than in the control MC-5 tumors that progress with normal angiogenesis. Three dimensional micro-MRI with the G6-(1B4M-Gd)(256) macromolecular MRI contrast agent distinguishes between the different types of angiogenesis and is predictive of the rapid accumulation and internalization of Herceptin in the WIBC-9 inflammatory breast cancer xenograft.

Barsky, S. H. (2002). The Molecular Basis of Inflammatory Breast Cancer. California Breast Cancer Research Program Symposium. Session presented for the California Breast Cancer Research Program, Oakland.

Introduction: Inflammatory breast cancer (IBC) is a poorly understood, little studied form of breast cancer which is very aggressive and particularly devastating in disadvantaged minority women. IBC is characterized by florid tumor emboli within lymphovascular spaces, a phenotype which distinguishes it from other forms of breast cancer. The molecular basis of this phenotype is the focus of this research.

Methods: Using a novel human-scid model of IBC, we have conceptually analyzed this phenotype in three parts.

Results:
1. The tumor cell embolus (IBC spheroid) forms on the basis of an intact and overexpressed E-cadherin /alpha-, beta-catenin axis which mediates tumor cell-tumor cell adhesion analogous to the embryonic blastocyst and accounts for both the compactness of the embolus and its complete dissolution with anti-E- cadherin antibodies, absent calcium, or E-cadherin dominant-negative mutant approaches. Dissolution of the tumor cell embolus by any of these approaches induces apoptosis via an anoikis pathway. The compactness of the embolus results in its resistance to chemotherapy / radiation therapy and its efficiency at metastasis formation and therefore therapeutic strategies which disadhere it are highly desirable.

2. The tumor cell embolus (IBC spheroid), in contrast, fails to bind the surrounding vascular endothelial cells because of complete absence of sialyl-Lewis X/A carbohydrate ligand-binding epitopes on its overexpressed MUC1 which are necessary for binding endothelial cell E-selectin. This natural tumor cell-endothelial cell aversion of the tumor cell embolus (IBC spheroid) further contributes to the compactness of the IBC spheroid and its passivity in metastasis dissemination. Experiments with purified glycosyltransferases which add sialyl-Lewis X/A to MUC1 on the IBC spheroids produce strong electrostatic repulsions which disrupt the E-cadherin homodimers and cause disadherence.

3. The tumor cell embolus finds itself within the vascular lumen in the first place because it stimulates a vascular channel to form around it rather than intravasating into a pre-existing lymphatic or capillary. The enveloping vascular channel does not form from angiogenesis but rather from vasculogenesis as evidenced by experiments where tumor cell emboli (IBC spheroids) are admixed with murine embryonal fibroblasts labeled with green fluorescent protein (GFP) and injected into scid mice. Tumor emboli are observed within lymphovascular spaces where the endothelial cells express vasculogenesis markers as well as endothelial markers. These endothelial cells also express GFP, evidence that they must have formed from the injected GFP-labeled murine embryonal fibroblasts.

Conclusion: The molecular basis of IBC provides a mechanism by which IBC bypasses the traditional steps of intravasation, dissemination and extravasation in its metastatic pathway and affords opportunities for therapeutic intervention.