Prognostic and Predictive Impact of Expression of the Angiogenic Markers CD105 and CD31 Expression in Patients with High Risk Breast Cancer (HRBC).
Authors: Gluz O. , Gaumann A. , Wild P. , Diallo-Danebrock R. , Liedtke C. , Ting E. , Mohrmann S. , Poremba C. , Nitz U. , Hartmann A. 
Published: December 2010

Abstract
Purpose: Several angiogenic factors have been reported to influence prognosis of breast cancer and spread to regional lymph nodes. CD105 (Endoglin) is expressed by human vascular endothelial cells and plays a major role in angiogenesis. Similarly, CD31 is a platelet endothelial cell adhesion molecule involved in normal and pathologic vessel function. In the prospective randomized WSG-AM-01 trial HRBC patients with more than 9 positive lymph nodes derived particular benefit from tandem high-dose (HD) rather than dose-dense (DD) chemotherapy with regard to both event-free (EFS) and overall survival (OS), particularly among tumors carrying a basal-like or HER2 molecular phenotype. The goal of the present study was to examine the interaction between angiogenic factors and efficacy of different dose intensification strategies in the WSG-AM-01 trial among both unselected patients as well as among distinct molecular disease subtypes.Methods: Immunohistochemical staining for CD31 (n=128) and CD105 (n=130) was performed to assess vascular surface area (VSA) separately for both factors using the Chalkley count method.Expression of estrogen (ER) and progesterone receptor (PR), HER2, Ki67, and epidermal growth factor receptor (EGFR) was analyzed immunohistochemically using tissue microarrays, allowing for stratification into molecular breast cancer subclasses (k-clustering k=5 by expression of 24 proteins). Correlation analysis between CD31 and CD105 expression and molecular subtypes was carried out using Pearson correlations. Univariate survival estimates were determined by Kaplan-Meier analysis and tested for significance by log rank statistics. Multivariate survival modeling was performed by a generalized Cox model, with linear proportional hazards terms in the first block and time-varying interactions in the second block.Results: Both VSA/CD 31 and VSA/CD105 showed significantly higher expression among HER-2 and basal-like breast cancer subtypes (p=0.007), as well as among cases wit increased Ki67 (p=0.005).Increased VSA/CD105 (above a median of 1.295) was associated with significantly decreases in both EFS (p=0.01) and OS (p=0.02). In multivariate analysis (including therapy, tumor size, age and grade as well as expression of ER, PR, HER-2 and Ki-67) increased VSA/CD 105 was an independent prognostic factor for decreased EFS (HR=1.68, p=0.05). Dose intensification showed significantly increased efficacy (for OS and EFS) only among patients with low VSA/CD105 tumors.Discussion: Expression of angiogenic markers may mirror/confer resistance to chemotherapy among patients with breast cancer, particularly in the context of dose intensified chemotherapy and may explain differences observed among distinct molecular breast cancer phenotypes. The correlation observed between angiogenic markers and distinct molecular subtypes may serve as a rationale for exploring antiangiogenic treatment options in patients carrying these tumors.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2154.