Predictive Biomarkers and Personalized Medicine Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC). ExperimentalDesign:Gene expressionprofiles for 70pretreatment specimens frommetastatic lesions of patients with chemorefractorymCRC receiving cetuximabmonotherapywere analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate. Results:Higher IGF-1R, higherGRB7, and lower INSIG2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60days (P1⁄40.01), 122 versus 57days (P1⁄40.011), and57 versus 156days (P<0.0001), favoringhigher IGF1R, higher GRB7, and lower INSIG2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P 1⁄4 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG2 expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P1⁄4 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001). Conclusions: These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings. Clin Cancer Res; 18(4); 1156–66. 2012 AACR.