Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR

Cancer Treat Rev. 2009 May;35(3):262-71. doi: 10.1016/j.ctrv.2008.11.005. Epub 2008 Dec 30.

Abstract

The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor progression of colorectal cancer (CRC). As a result, the EGFR has evolved as a relevant target in the treatment of metastatic CRC. KRAS serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. The presence of activating KRAS mutations has been identified as a potent predictor of resistance to EGFR-directed antibodies such as cetuximab or panitumumab. These agents should therefore be applied only in tumors with a wild-type status of the KRAS gene. Further parameters of resistance are lack of EGFR amplification, PTEN loss or BRAF mutation. However, they are less well studied or associated with less consistent data and therefore require prospective analyses before integration into clinical decision making. Future studies need to identify patterns of single or multiple mutations to further increase the power of patient selection for anti-EGFR therapy. While molecular parameters help to predict treatment efficacy upfront, skin toxicity has been accepted as an independent predictor of response during exposure to anti-EGFR therapy.

Publication types

  • Review

MeSH terms

  • Adenocarcinoma / chemistry
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neoplasm / immunology
  • Antibodies, Neoplasm / therapeutic use*
  • Cetuximab
  • Colorectal Neoplasms / chemistry
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / chemistry
  • Colorectal Neoplasms, Hereditary Nonpolyposis / drug therapy
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Mutational Analysis
  • Drug Delivery Systems
  • Drug Eruptions / etiology
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / analysis
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • ErbB Receptors / immunology
  • Gene Dosage
  • Genes, erbB-1*
  • Genes, ras*
  • Humans
  • Mutation
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • PTEN Phosphohydrolase / analysis
  • PTEN Phosphohydrolase / genetics
  • Panitumumab
  • Patient Selection
  • Proto-Oncogene Proteins / analysis
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins B-raf / analysis
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction / drug effects
  • ras Proteins / analysis
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics*
  • ras Proteins / immunology

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neoplasm
  • KRAS protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Panitumumab
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab