P5-01-19: Endothelin-1 Expression in Breast Cancer Tissue, Surrounding Stroma, Correlation with Tumor Microvessel Density and Clinical Outcome.

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Abstract Background: Endothelin-1 (ET-1) is a peptide which regulates normal biological processes such as vascular tone. In addition, endothelin signaling pathway is dysregulated in pathophysiological conditions such as cancer and fibrosis. It has been shown that endothelin-1 is expressed in breast cancer tissue but little is known with regard to ET-1 expression in surrounding tumor stroma. In the present study, we investigated ET-1 expression in breast tumor cells, surrounding stroma, association with tumor microvessel density (MVD) and impact on clinical outcome. Materials and Methods: We conducted a retrospective, multicenter study. Patients from 3 medical centers with histologically documented stage I-III invasive breast cancer were included in the study. Paraffin embedded formalin fixed breast cancer tissue and surrounding stroma were evaluated for ET-1 and CD34 (marker for MVD) by IHC. ET-1 cytoplasmic expression was scored as positive (3+ by IHC) or negative (0, 1+, 2+). Stained vessels by CD34 were counted in five consecutive fields at 40 x magnification and their mean was recorded. Demographics, clinical data and recurrence free interval (RFI) in months were available for statistical analysis. Results: The study included 92 patients with average age of 55 years at diagnosis. Median follow up of patients at the time of analysis was 72 months. Total of 29 patients experienced disease progression ( 17 locoregional and 12 distant). Tumor ET-1 expression positively correlated with earlier stage: odds ratio (OR) = 22 for stage I and OR=20 for stage II as compared with stage III. Positive ET-1 staining in tumor was detected in 72.8 % of cases, while ET-1 positive expression in stroma was detected only in 6.5% of cases. Interestingly, all ET-1 stroma positive tumors were estrogen receptor (ER) positive. The means of CD34 were not different according to ET-1 expression either in the tumor or stroma. Triple negative breast cancer tumors exhibited higher MVD (p=0.0177). In the logistic regression model relating ET-1 expression in tumor to clinical variables, ET-1 positive tumors showed a trend for the association with higher relapse rate (p=0.058). Multivariate analysis suggested that there was no significant difference in the recurrence free interval (RFI) between the ET-1 positive and ET-1 negative groups (long-rank test p-value = 0.71). Survival analysis identified stage as a significant predictor of RFI in the Cox proportional hazard model that included ET-1 expression and other clinical variables. Conclusions: The significant predictor for ET-1 expression in the tumor was early stage. High tumor ET-1 expression was more common in patients who experienced breast cancer recurrence. No association was found between ET-1 expression and MVD, and between ET-1 expression and time to recurrence. Further studies with larger sample size are needed to better delineate a role of ET-1 as prognostic biomarker in early stage breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-19.