Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab

Abstract

Purpose To study the power of the epidermal growth factor receptor (EGFR) epiregulin (EREG) and amphiregulin (AREG) ligands’ expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab and irinotecan. Patients and Methods Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting. Results In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95% CI, 0.274 to 0.609; P < .001; time-dependent c-index [Cτ index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; Cτ index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; Cτ index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; Cτ index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation. Conclusion Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.