Abstract #2743: Gene expression module associated with Insulin-like Growth Factor 1 (IGF1) pathway activation predicts poor response to tamoxifen in women with ER+/HER2- early breast cancer (BC).

Background: Insulin-like Growth Factor 1 (IGF1) signaling has been shown to be crucial for tumor transformation and survival of malignant cells. In BC, IGF1 pathway activation was related to tamoxifen resistance in estrogen receptor (ER)-positive cell lines and in vivo mouse models. In this present study, we sought to investigate the clinical relevance of IGF1 pathway activation in a large homogenous data set of ER+/HER2- BC patients with well-annotated microarray data and long clinical follow-up. Material and Methods: The IGF1 pathway module was developed in silico by selecting genes that were specifically correlated with the expression levels of IGF1 gene without looking at gene annotation and clinical outcome. The association between IGF1 module and clinical outcome was investigated using several publicly available datasets including 590 systemically untreated and 383 tamoxifen only treated node negative and node positive ER+/HER2- early BC patients. Low (luminal A) vs high (luminal B) proliferative ER+/HER2- BC subtypes were defined based on the Genomic Grade Index (GGI). Results: IGF1 module was composed of 142 IGF1 pathway related genes. IGF1 pathway activation was significantly associated with high-proliferative ER+/HER2- tumors (luminal B). In the van de Vijver and Wang datasets, the IGF1 module demonstrated a significant correlation (Pearson correlation 0.619 and 0.601, respectively) with an IGF1 signature developed by in vitro IGF1 stimulation of MCF7 cells lines (Creighton et al JCO 2008). IGF1 pathway activation was associated with worse distant metastasis free survival (DMFS) in systemically untreated and tamoxifen-only treated women with ER+/HER2- BC (P<.001 and P<.001 respectively). The interaction test between IGF1 activation and treatment with tamoxifen was significant in the univariate model. In multivariate analysis, IGF1 activation was an independent prognostic factor for poor outcome beyond standard clinico-pathological characteristics and proliferation captured by GGI. Conclusion: IGF1 signaling activation predicts poor clinical outome in untreated and tamoxifen only treated women with ER+/HER2- BC. Inhibitors of IGF1 signaling should be explored in IGF1 module-enriched ER+/HER2- BC patients.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2743.