Tumor stromal vascular endothelial growth factor A is predictive of poor outcome in inflammatory breast cancer

Abstract

BackgroundInflammatory breast cancer (IBC) is a highly angiogenic disease; thus, antiangiogenic therapy should result in a clinical response. However, clinical trials have demonstrated only modest responses, and the reasons for these outcomes remain unknown. Therefore, the purpose of this retrospective study was to determine the prognostic value of protein levels of vascular endothelial growth factor (VEGF-A), one of the main targets of antiangiogenic therapy, and its receptors (VEGF-R1 and -R2) in IBC tumor specimens.Patients and MethodsSpecimens from IBC and normal breast tissues were obtained from Algerian patients. Tumor epithelial and stromal staining of VEGF-A, VEGF-R1, and VEGF-R2 was evaluated by immunohistochemical analysis in tumors and normal breast tissues; this expression was correlated with clinicopathological variables and breast cancer-specific survival (BCSS) and disease-free survival (DFS) duration.ResultsFrom a set of 117 IBC samples, we evaluated 103 ductal IBC tissues and 25 normal specimens. Significantly lower epithelial VEGF-A immunostaining was found in IBC tumor cells than in normal breast tissues (P <0.01), cytoplasmic VEGF-R1 and nuclear VEGF-R2 levels were slightly higher, and cytoplasmic VEGF-R2 levels were significantly higher (P = 0.04). Sixty-two percent of IBC tumors had high stromal VEGF-A expression. In univariate analysis, stromal VEGF-A levels predicted BCSS and DFS in IBC patients with estrogen receptor-positive (P <0.01 for both), progesterone receptor-positive (P = 0.04 and P = 0.03), HER2+ (P = 0.04 and P = 0.03), and lymph node involvement (P <0.01 for both). Strikingly, in a multivariate analysis, tumor stromal VEGF-A was identified as an independent predictor of poor BCSS (hazard ratio [HR]: 5.0; 95% CI: 2.0-12.3; P <0.01) and DFS (HR: 4.2; 95% CI: 1.7-10.3; P <0.01).ConclusionsTo our knowledge, this is the first study to demonstrate that tumor stromal VEGF-A expression is a valuable prognostic indicator of BCSS and DFS at diagnosis and can therefore be used to stratify IBC patients into low-risk and high-risk groups for death and relapses. High levels of tumor stromal VEGF-A may be useful for identifying IBC patients who will benefit from anti-angiogenic treatment.

Cancer prevention and therapy through the modulation of the tumor microenvironment

“…VEGF alone can initiate the angiogenic cascade [124]. VEGF is secreted by most human cancers [124], and VEGF expression can be correlated with a poor prognosis in ovarian [100] and other types of cancer tumors [125–128]. …”

Application of a Novel Microvascular Imaging Technique in Breast Lesion Evaluation

“…However, invasive malignant tumors display rapid growth, which requires nutrition supplied by newly formed microvessels, a process called angiogenesis (Fox et al 2007;Weidner et al 1991). Vascular endothelial growth factors and other angiogenic factors are highly expressed in malignant breast tumors and promote angiogenesis in breast tumors (Arias-Pulido et al 2012;Chen et al 2013;Gasparini 2000). Therefore, microvascular density is significantly higher in malignant breast lesions as opposed to benign lesions.…”

Inflammatory Breast Neoplasms: A Systematic Review

“…m in a n t s 5 , 2 0 , 2 5 ( t h r e e s t u d i e s ) a n d p r o g n o stics 3,8,9,11,22,24,27,29 (eight studies). E-cadherin accumulation and subsequent overexpression is responsible for both MARY-X spheroids as well as the lymph-vascular emboli and fosters.…”

“…Prognostics-oriented studies explore mainly biological factors that are good prognostics markers 3,8,9,11,22,24,27,29 .…”