Effects of Bevacizumab in Patients With Inflammatory and Locally Advanced Breast Canc
 

http://www.jco.org/cgi/content/abstract/24/5/769
Antiangiogenic and Antitumor Effects of Bevacizumab in Patients With Inflammatory and Locally Advanced Breast Cancer

Suparna Bonthala Wedam, Jennifer A. Low, Sherry X. Yang, Catherine K. Chow, Peter Choyke, David Danforth, Stephen M. Hewitt, Arlene Berman, Seth M. Steinberg, David J. Liewehr, Jonathan Plehn, Arpi Doshi, Dave Thomasson, Nicole McCarthy, Hartmut Koeppen, Mark Sherman, JoAnne Zujewski, Kevin Camphausen, Helen Chen, Sandra M. Swain


From the Cancer Therapeutics Branch, Molecular Imaging Program, Surgery Branch, Laboratory of Pathology, Medical Oncology Clinical Research Unit, Biostatistics and Data Management Section, and Radiation Oncology Branch, Center for Cancer Research; Cardiovascular Branch, Center for Cancer Research, National Heart, Blood, and Lung Institute; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis; Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Bethesda, MD; University of Auckland, Auckland, New Zealand; Department of Pathology, Genentech Inc, South San Francisco, CA

Address reprint requests to: Sandra M. Swain, MD, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 8901 Wisconsin Avenue, Building 8, Rm 5101, Bethesda, MD 20889-5015; e-mail: swains@mail.nih.gov

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis.

PATIENTS AND METHODS: Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7.

RESULTS: A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone.

CONCLUSION: Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.

This work was performed as part of the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (Bethesda, MD).

Presented in part at the Lynn Sage Cancer Symposium, Chicago, IL, September 2003; the Keystone Symposium, Santa Fe, NM, January 2004; the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004; the Annual Meeting of International Society for Magnetic Resonance in Medicine, Miami, FL, May 2005; and the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.