title: Therapeutic Strategies in Diseases of the Digestive Tract - 2015 and Beyond Targeted Therapies in Colon Cancer Today and Tomorrow.
abstract: BACKGROUND
  Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state. After the introduction of the anti-VEGF MAB bevacizumab, the FDA approved with ramucirumab the second antiangiogenic MAB for the mCRC treatment. Further new drugs are on the horizon and new diagnostic tools will be introduced soon.
  
  
  CONCLUSIONS
  Molecular heterogeneity of mCRC has been recognized as pivotal in the evolution of clonal populations during anti-EGFR therapies. Mutations in RAS genes predict a lack of response to anti-EGFR MABs. Mutations in the mitogen-activated protein kinase-phosphoinositide 3-kinase pathways like BRAF or PIK3CA mutations or HER2/ERBB2 or MET amplifications bypass EGFR signaling and also may confer resistance to anti-EGFR MABs. HER2/ERBB2 amplification is a further driver of resistance to anti-EGFR MABs in mCRC. The phase II study of HER2 Amplification for Colo-Rectal Cancer Enhanced Stratification (HERACLES) discovers that a dual HER2-targeted therapy may be an option for HER2-amplified mCRC. The mismatch repair deficiency predicts responsiveness to an immune checkpoint blockade with the anti-PD-1 immune checkpoint inhibitor pembrolizumab.
  
  
  CONCLUSIONS
  The understanding of primary (de novo) and secondary (acquired) resistance to anti-EGFR therapies, new targeted therapies, immuno-oncology and about predictive biomarkers in mCRC is guiding the development of rational therapeutic strategies. Combinations of targeted therapies are necessary to effectively treat drug-resistant cancers. Liquid biopsy is an upcoming new tool in the primary diagnosis and follow-up analysis of mutations in circulating tumor DNA.
authors.affiliation: Department of Medicine, Universitx00E4;tsklinikum Knappschaftskrankenhaus, Bochum, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pohl
authors.forename: Wolff
authors.initials: W
authors.lastname: Schmiegel
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D066246:ErbB Receptors / Q000276:immunology; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000188:drug therapy / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D000096662:Ramucirumab; C582435:pembrolizumab