title: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.
abstract: PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
authors.affiliation: Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Saletti
authors.forename: Sara
authors.initials: S
authors.lastname: De Dosso
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D000077544:Panitumumab; D018579:Patient Selection; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology; D012189:Retrospective Studies; D000077157:Sorafenib; D013557:Switzerland; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D009536:Niacinamide; D000077544:Panitumumab; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab