Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The 
aim of this study was to investigate the effects of baseline plasma AREG levels 
in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on 
treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. 
Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The 
clinical findings were further validated using an in vitro model of CRC. Among 
35 patients, the progression-free survival (PFS) was significantly inferior in 
patients with high AREG than in those with low AREG levels: 10.9 vs. 
24.2 months, respectively (p = 0.008). However, after failure of first-line 
chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; 
p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and 
Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC 
cell lines tested, AREG significantly decreased the anti-proliferative effect of 
cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring 
cetuximab resistance with gradual exposure for more than 6 months, AREG neither 
increased colony formation nor activated AKT and ERK after cetuximab treatment. 
Our results suggest that plasma AREG is a potential biomarker to predict 
clinical outcomes after cetuximab-based chemotherapy.