title: A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshida
authors.forename: Takaya
authors.initials: T
authors.lastname: Shimura
authors.forename: Mikinori
authors.initials: M
authors.lastname: Sato
authors.forename: Masahide
authors.initials: M
authors.lastname: Ebi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takeyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000068818:Cetuximab; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008024:Ligands; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab