title: Comparison of the prognosis indication of VEGFR-1 and VEGFR-2 and Tie2 receptor expression in breast carcinoma.
abstract: The degree of angiogenesis in breast cancer has previously been shown to be an indicator of prognosis, and tumor microvasculature is a candidate target for new antiangiogenic therapies. The aim of this study was to investigate the prognostic value of vascular endothelial growth factor (VEGF) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and Tie2/tek receptor tyrosine kinase in breast carcinoma. VEGF receptors and Tie2 expression was investigated using immunohistochemical assays with monoclonal antibodies on frozen sections in a series of 918 and 909 patients respectively. VEGFR-1 and VEGFR-2 and Tie2 were correlated with long-term (median, 11.3 years) patients' outcome. Univariate (Kaplan-Meier) analysis showed that VEGFR-1 positive tumor surface (cutoff = 5%) was significantly correlated with high metastasis risk (p=0.03) and relapse (p<0.01) in all patients, and in those with node negative tumors (p<0.001 and p<0.01 respectively), but not with overall survival. In contrast Tie2 positive tumor surface (cutoff = 7%) was significantly correlated with poor overall survival (p=0.025) and also with high metastasis risk particularly among node negative patients (p<0.01). Moreover, Tie2 immunoexpression was significantly predictive of relapse (p=0.003) in the node negative subgroup (p=0.02). In multivariate analysis (Cox model), VEGFR-1 and Tie2 immunoexpressions were identified as independent prognostic indicators. In contrast, univariate analysis showed that VEGFR-2 positive tumor surface (cutoff = 10%) was not correlated with survival or with metastasis and relapse risk. Our results suggest that VEGFR-1 and Tie2 immunohistochemical expression permits the identification of patients with poor outcome, and particularly node negative ones with a high risk for metastasis and relapse. VEGFR-1 and Tie2 immunodetection may also be considered as potential tools for selecting patients who could benefit in the future from specific antiangiogenic therapy interfering with VEGFR-1 and Tie2 activation pathways.
authors.affiliation: Department of Pathology, Hôpital Nord, Université de la Méditerranée, Boulevard Pierre Dramard, 13916 Marseille, France. severine.meunier-carpentier@ap-hm.fr
authors.forename: Séverine
authors.initials: S
authors.lastname: Meunier-Carpentier
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Dales
authors.forename: Amina
authors.initials: A
authors.lastname: Djemli
authors.forename: Stéphane
authors.initials: S
authors.lastname: Garcia
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnier
authors.forename: Lucile
authors.initials: L
authors.lastname: Andrac-Meyer
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Lavaut
authors.forename: Claude
authors.initials: C
authors.lastname: Allasia
authors.forename: Colette
authors.initials: C
authors.lastname: Charpin
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011379:Prognosis; D042787:Receptor, TIE-2 / Q000096:biosynthesis*; D016019:Survival Analysis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
chemical_list: D000911:Antibodies, Monoclonal; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2