Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR.
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.
Heinemann
Volker
V
Department of Hematology/Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchionini-Street 15, 81377 Munich, Germany.
Stintzing
Sebastian
S
Kirchner
Thomas
T
Boeck
Stefan
S
Jung
Andreas
A
D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics; D004252:DNA Mutational Analysis; D016503:Drug Delivery Systems; D003875:Drug Eruptions / Q000209:etiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D018628:Gene Dosage; D018773:Genes, erbB-1; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics; D000077544:Panitumumab; D018579:Patient Selection; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab