Use of endothelin-A-receptor expression to predict poor response to primary chemotherapy in locally advanced breast cancer

Abstract

576 Background: Endothelin-1 (ET-1) and its receptors (ETAR and ETBR), referred to as the ET-axis, are overexpressed in breast carcinomas and seem to influence tumorigenesis and tumor-progression. Failure of breast carcinomas to respond to treatment is still a major impediment to successful cytotoxic therapy and to date no tumor biological factor is available for clinical use predicting chemotherapy response in breast cancer. The aim of our study was to determine the predictive value of ET-axis protein expression in breast carcinomas for chemotherapy response. Methods: 44 patients with locally advanced breast cancer who took part in a prospective phase III study evaluating a high-dose primary chemotherapy of epirubicin and cyclophosphamide were included. Expression of ET-1, ETAR and ETBR was determined by semiquantitative immunohistochemical (IH) analysis of paraffin-embedded breast cancer tissue from the prechemotherapy tru-cut biopsies. Results: IH staining was positive for ET-1 in 61.5%, for ETAR in 35% and for ETBR in 35.9% of breast carcinomas. The overall clinical response rate was 58.1%, the overall pathological response rate was 72.7%. Pathological response to primary chemotherapy was significantly decreased in ETAR-positive patients (p=0.002). Pathological “no change” was obtained in 50% of ETAR-positive as compared to 7.7% of ETAR-negative patients. Logistic regression confirmed ETAR as an independent predictive marker for pathological response (p=0.009). Also, ETBR expression correlated with pathological non-response (42.9%), although statistical significance was not reached (p=0.065). Clinical response to chemotherapy was reduced in ETAR-positive patients as compared to ETAR-negative patients (46.2% vs. 73.1%, respectively; p=0.098). Conclusions: Our findings suggest that expression of ET receptors and especially of ETAR in breast cancer is associated with chemotherapy resistance. Thus, determination of ETAR status may serve as a predictive marker for identifying patients with a poor chance of response to chemotherapy and, therefore, potential candidates for more individualized treatments. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories