[The RAS paradox of the EGFR-targeted therapy in colorectal cancer].
During the carcinogenesis of colorectal cancer in about half of the cases K-RAS, while much less frequently B-RAF mutation occur in early adenomas. While K-RAS mutant tumors are more likely present in male patients, B-RAF mutant tumors develop more frequently in females and are independent of the microsatellite status. Colorectal cancers are characterized by EGFR expression; the gene is not mutated, rarely amplified and increased copy number is due to chromosomal polysomy. This phenotype/genotype of colorectal cancer lent support to the introduction of anti-EGFR antibody therapies. For a while positive EGFR expression status of the tumor was the basis of patient selection for these targeted therapies in colorectal cancer. Monotherapies with the two available anti-EGFR antibodies of chemoresistant colorectal cancers resulted in appr. 10% objective response rate, which was independent of the level of EGFR expression. In case of panitumumab it was discovered that the efficacy of this targeted therapy depends on the K-RAS mutant status of the tumors. Furthermore, preliminary data suggest that cetuximab combined with chemotherapy is effective also exclusively in K-RAS wild-type tumors. Based on these data it is safe to say that K-RAS mutant status of colorectal cancer is a negative predictor for EGFR-targeted therapies of colorectal cancer. Accordingly, it is necessary to determine the K-RAS status of colorectal cancer before making therapeutic decisions.
Tímár
József
J
Országos Onkológiai Intézet 1122 Budapest Ráth György u. 7-9. jtimar@oncol.hu
Láng
István
I
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D008297:Male; D009154:Mutation / Q000187:drug effects; D009369:Neoplasms / Q000235:genetics; D000077544:Panitumumab; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077544:Panitumumab; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab