Abstract 2697: Analysis of the correlation between gene expression of IGF-pathway components and benefit from cetuximab (Erbitux™) in metastatic colorectal cancer patients
Authors: Huang Fei , Xu Li-An , Khambata-Ford Shirin 
Published: February 2011

Abstract
OBJECTIVE: There is considerable evidence showing cross-talk between the epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) pathways. This analysis was carried out to examine the correlation between the gene expression levels of IGF pathway components and the clinical benefit from the anti-EGFR monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC) patients; and to look for the factors contributing to non-benefit from cetuximab in K-Ras wild type (WT) patients, further seeking the treatment options for this sub-population.
EXPERIMENTAL DESIGN: Gene expression profiling data for the components of IGF pathway and K-Ras mutational status are available from 70 pre-treatment tumor biopsies from patients with refractory mCRC receiving cetuximab monotherapy (Khambata-Ford et al., 2007).
RESULTS: In this cohort of mCRC, patients with tumors expressing high level of IGF-IR or GRB7 were associated with longer progression-free survival (PFS) with cetuximab than patients with low expression levels of these genes. In addition, patients with tumors that express low level of insulin inducible gene 2 (INSIG2), insulin receptor (INSR), IGF-1 or IGF binding protein 3 (IGFBP3) were found to have a longer PFS and higher disease control rate than patients with high expression levels of these genes. For example, median PFS was 115 days in INSIG2 low-expressing tumors and 58 days in INSIG2 high-expressing tumors (log-rank p=0.0029, hazard ratio=0.45); and the disease control rate was 51.4% and 11.4%, respectively, for patients with INSIG2 low-expressing tumors vs. INSIG2 high-expressing tumors (Fisher exact p=0.0006). Furthermore, among patients with K-Ras WT tumors, a significant difference in disease control rate was observed for INSIG2 low- and high-expressing tumors (76.2 % vs. 18.2 %, Fisher exact p=0.0002). Additionally, patients with K-Ras WT tumors that have a high gene expression of IGF-1R had a significantly higher disease control rate (62.5%) than patients with low expression (26.3%) (Fisher exact p=0.03) and longer PFS (log-rank p= 0.01, hazard ratio=2.45, and median PFS, 122 days vs. 60 days, respectively).
CONCLUSION: A statistically significant association was observed between the gene expression of some key components of the IGF pathway and benefit from cetuximab in mCRC. In patients with K-Ras WT tumors, high expression of IGF-1R and GRB7 are potential predictive factors for clinical benefit whereas low expression of IGF-1 and INSIG2 are potential predictive factors for resistance to cetuximab. Our data suggest that IGF pathway plays an important role in benefit from the anti-EGFR therapy cetuximab, and that targeting IGF-1R/IR may prove valuable treatment option in K-Ras WT mCRC patients that not benefit from cetuximab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2697.