Abstract
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.
Highlights
Palliative first-line chemotherapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, or panitumumab, combined with conventional cytotoxic chemotherapy, has shown preferable outcomes in phase III trials[1,2,3,4]
Our results indicated that high baseline plasma AREG levels could predict progression-free survival (PFS) after first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS/BRAF wild-type colorectal cancer
Our in vitro study indicated that AREG significantly enhanced the growth of cetuximab-sensitive RAS/BRAF wild-type colorectal cancer cell lines with increased phosphorylation of AKT and ERK1/2
Summary
Palliative first-line chemotherapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibody, cetuximab, or panitumumab, combined with conventional cytotoxic chemotherapy, has shown preferable outcomes in phase III trials[1,2,3,4]. In clinical practice, the treatment response is varied even among RAS/BRAF wild-type patients. AREG is known to act competitively with anti-EGFR monoclonal antibodies and activate downstream signaling, and may be involved with cetuximab r esistance[10]. In some studies, conflicting results have been reported on the effects of AREG on anti-EGFR treatment o utcomes[11,12,13]. In this study, we aimed to investigate the effects of baseline plasma AREG levels in patients with colorectal cancer treated with palliative first-line cetuximab plus FOLFIRI regimen and subsequent second-line chemotherapy. We conducted an in vitro study to further define the molecular mechanisms of AREG in cetuximab-naïve and cetuximab-resistant colorectal cancer cell lines
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