P2-11-11: IGFBP Ratio Confers Resistance to IGF Targeting and Correlates with Increased Invasion and Poor Outcome in Breast Tumors.

Abstract

Abstract Purpose: To assess the role of insulin-like growth factor binding protein 5 (IGFBP-5) as a marker of relapse and survival in breast cancer tumors. Experimental Design: Targeted regulation of IGFBP-5 was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/InsR inhibitor, BMS-536924 and examined by comparative microarray analysis, western and ELISA. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 84 breast cancer patients to examine correlative associations with invasive tumor fraction and overall survival (OS). The expression ratio of IGFBP-5/IGFBP-4 (BPR) was determined in multiple breast tumor cohorts for univariate analysis. Results: IGFBP-5 was markedly upregulated and highly localized to the membrane in MCF-7R4 resistant cells. When compared to pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In an independent cohort of breast cancer patients, IGFBP-5 protein levels correlated directly with invasion and OS. In univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS) and OS were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 and tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS. Conclusion: IGFBP-5 expression is a marker of poor outcome in breast cancer patients. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to IGF-1R-targeted therapies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-11.