Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer

Cancer Sci. 2015 May;106(5):604-10. doi: 10.1111/cas.12642. Epub 2015 Apr 29.

Abstract

Skin toxicity is a known clinical signature used to predict the prognosis of anti-epidermal growth factor receptor (EGFR) antibody treatment in metastatic colorectal cancer (mCRC). There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients. Between August 2008 and August 2011, pretreatment serum samples were obtained from KRAS wild-type (WT) patients who received anti-EGFR antibody treatment. Serum levels of ligands were measured by ELISA. A total of 103 KRAS WT patients were enrolled in the study. Progression-free survival and overall survival of patients with a high grade (grade 2-3) of skin toxicity were significantly longer than those with a low grade (grade 0-1) of skin toxicity (median progression-free survival, 6.4 months vs 2.4 months, P < 0.001; median overall survival, 14.6 months vs 7.1 months, P = 0.006). There were significant differences in distribution of serum levels of epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) between groups of low/high grade of skin toxicity (P < 0.048, P < 0.012, P < 0.012, respectively). In addition, serum levels of HGF, EREG, and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran-Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG, and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment, which contribute to improvement of the management of skin toxicity and survival time in mCRC patients.

Keywords: Colorectal cancer; EGFR; KRAS; ligands; skin toxicity.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amphiregulin
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Pharmacological / blood*
  • Cetuximab
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • EGF Family of Proteins / blood
  • Epiregulin / blood
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism
  • Female
  • GTP Phosphohydrolases / genetics
  • Hepatocyte Growth Factor / blood
  • Humans
  • Insulin-Like Growth Factor I / analysis
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Mutation
  • Panitumumab
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Skin / drug effects*
  • Skin / pathology
  • Transforming Growth Factor alpha / blood
  • Treatment Outcome
  • ras Proteins / genetics

Substances

  • AREG protein, human
  • Amphiregulin
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Biomarkers, Pharmacological
  • EGF Family of Proteins
  • EREG protein, human
  • Epiregulin
  • HGF protein, human
  • KRAS protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Transforming Growth Factor alpha
  • Hepatocyte Growth Factor
  • Insulin-Like Growth Factor I
  • Panitumumab
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab