A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies

J Cancer Res Clin Oncol. 2013 Mar;139(3):367-78. doi: 10.1007/s00432-012-1340-x. Epub 2012 Oct 26.


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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies / pharmacology
  • Antibodies / therapeutic use*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / metabolism
  • Carcinoma / diagnosis*
  • Carcinoma / drug therapy
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cetuximab
  • Clinical Trials, Phase III as Topic
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • ErbB Receptors / agonists
  • ErbB Receptors / immunology*
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Immunohistochemistry* / methods
  • Ligands
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Panitumumab
  • Predictive Value of Tests
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Antibodies
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • KRAS protein, human
  • Ligands
  • Proto-Oncogene Proteins
  • Panitumumab
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab