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Gene Expression Profile and Angiogenic Markers Correlate with Response to Neoadjuvant Bevacizumab Followed by Bevacizumab plus Chemotherapy in Breast Cancer

Authors' Affiliations: ¹ National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, ² Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, ³ Department of Molecular Biology and Bioinformatics, Genentech, Inc., South San Francisco, California, and ⁴ Washington Cancer Institute, Washington Hospital Center, Washington, District of Columbia

Requests for reprints: Sandra M. Swain, Washington Cancer Institute, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20001. E-mail: SandraMSwain{at}medstar.net or Sherry X. Yang, National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892. Phone: 301-402-8157; Fax: 301-480-4679; E-mail: xy32m{at}nih.gov.

Purpose: To identify biomarkers and gene expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD).

Experimental Design: Twenty patients with inflammatory breast cancer and one patient with locally advanced breast cancer received one cycle of bevacizumab followed by six cycles of bevacizumab plus docetaxel-doxorubicin before surgery. Baseline angiogenic/tumor markers were examined by immunohistochemistry and gene expression profiles were measured by Agilent Whole Human Genome arrays. All were assessed for clinical response.

Results: Fourteen patients (67%, 95% confidence interval, 43-85.4%) had PR, five had SD, and two had PD. Expression of CD31 and platelet-derived growth factor receptor-β (PDGFR-β) in the tumor vasculature by immunohistochemistry was significantly associated with response (PR versus SD/PD; CD31 median, 33.5 versus 13.2; P = 0.0004; PDGFR-β median, 5.9 versus 0.6; P = 0.01). Tumor VEGF-A showed a trend towards association with response (2.65 versus 0.25; P = 0.04). pVEGFR2(Y996), pVEGFR2(Y951), MVD, Ki67, apoptosis, grade, ER, HER-2/neu, and p53 were not associated with response. Twenty-six of 1,339 Gene Ontology (GO) classes at the gene transcriptional level were differentially expressed between patients with PR and SD/PD (P < 0.005). Representative significant GO classes include spindle (11 genes; P = 0.001), vascular endothelial growth factor receptor activity including PDGFR-β (5 genes; P = 0.002), and cell motility including CD31 (80 genes; P = 0.005).

Conclusions: Baseline CD31, PDGFR-β, and GO classes for vascular endothelial growth factor receptor activity and mitosis were significantly associated with response to bevacizumab followed by bevacizumab plus chemotherapy.