Biomarkers and anti-EGFR therapies for KRAS wild-type metastatic colorectal cancer.
Therapy for metastatic colorectal cancer has been improved in terms of response rate, time to progression and overall survival by the emergence of anti-EGFR monoclonal antibodies (cetuximab and panitumumab) in combination with standard cytotoxic chemotherapy (oxaliplatin or CPT-11-based combinations). However, the benefits of cetuximab and panitumumab are confined to KRAS wild-type (KRAS-wt) colorectal tumours; KRAS-mutated tumours rarely respond to these drugs. Of all colorectal tumours, 65% are KRAS-wt tumours, but anti-EGFR therapies are effective for only 60-70% of these. Therefore, other biomarkers and molecular pathways must be involved in the response to anti-EGFR therapies in KRASwt colorectal tumours. Factors that may explain the lack of response include EGFR ligands, EGFR phosphorylation levels, the number of EGFR copies, the status of the KRAS effector B-RAF and the alternative intracellular PIK3CA/ PTEN/AKT and JAK/STAT signalling pathways. A battery of biomarkers is needed to select the patients that will be most sensitive to anti-EGFR therapies. Such patterns may be a novel and cost-effective tool to develop tailored treatments. This manuscript will review biomarkers and molecular pathways that are involved in the tumour response to anti-EGFR therapies.
García-Sáenz
Jose A
JA
Servicio de Oncología Médica, Hospital Clínico Universitario San Carlos, Madrid, Spain. jagsaenz@yahoo.com
Sastre
Javier
J
Díaz-Rubio García
Eduardo
E
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000378:metabolism*; D049109:Cell Proliferation; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011905:Genes, ras; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D008024:Ligands; D000077544:Panitumumab; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab