PURPOSE: Although KRAS mutation has been identified as a negative predictive 
biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the 
efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR 
antibodies work by blocking ligand binding, but the significance of EGFR ligands 
in mCRC has not been completely described. This study was conducted to identify 
the correlation between all seven EGFR ligands and clinical outcomes in mCRC 
treated with anti-EGFR antibodies. Furthermore, we determined an appropriate 
predictive strategy for anti-EGFR antibodies using these EGFR ligands.
METHODS: Among 36 mCRC patients who had been treated with cetuximab or 
panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated 
properly as the second and further lines and analyzed the relationship between 
immunoreactivity to seven EGFR ligands and clinical outcomes.
RESULTS: Good clinical outcomes were associated with immunoreactivity against 
amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), 
transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients 
with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, 
TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 
0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer 
progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when 
compared with patients with immunoreactivity against zero or one ligand.
CONCLUSIONS: Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, 
TGF-α, and EREG) might be a novel predictive biomarker and may help optimize 
patient selection for cetuximab and panitumumab therapy in patients with mCRC.