title: Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis.
abstract: BACKGROUND
  Wild type RAS (RAS-wt) status is predictive of the activities of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (C) and panitumumab (P). We examined the impact of C and P on progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) in advanced colorectal cancer (CRC) patients who have RAS-wt/BRAF-mutant (BRAF-mut) status.
  
  
  METHODS
  Randomised trials that compared C or P plus chemotherapy (or C or P monotherapy) with standard therapy or best supportive care (BSC) were included. We used published hazard ratios (HRs) if they were available, or we derived treatment estimates from other survival data. Pooled estimates of the treatment efficacy of anti-EGFR-based therapy with C or P for the RAS-wt/BRAF-mut subgroup were calculated with the random-effect inverse variance weighted method. All statistical tests were two-sided.
  
  
  RESULTS
  Nine phase III trials and one phase II trial (six first-line and two second-line trials, plus two trials involving chemorefractory patients), that included 463 RAS-wt/BRAF-mut CRC patients, were analysed. Overall, the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS (HR, 0.88; 95% confidence interval (CI), 0.67-1.14; p=0.33), OS (HR, 0.91; 95% CI, 0.62-1.34; p=0.63) and ORR (relative risk, 1.31; 95% CI 0.83-2.08, p=0.25) compared with control regimens.
  
  
  CONCLUSIONS
  C- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients. These findings support BRAF mutation assessment before initiation of treatment with anti-EGFR monoclonal antibodies.
authors: Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: filippo.pietrantonio@istitutotumori.mi.it.
authors: Filippo
authors: F
authors: Pietrantonio
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: faupe@libero.it.
authors: Fausto
authors: F
authors: Petrelli
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: artefice2003@hotmail.com.
authors: Andrea
authors: A
authors: Coinu
authors: Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: maria.dibartolomeo@istitutotumori.mi.it.
authors: Maria
authors: M
authors: Di Bartolomeo
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: karenbf_it@yahoo.it.
authors: Karen
authors: K
authors: Borgonovo
authors: Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: claudia.maggi@istitutotumori.mi.it.
authors: Claudia
authors: C
authors: Maggi
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: mary_cabiddu@yahoo.it.
authors: Mary
authors: M
authors: Cabiddu
authors: Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: roberto.iacovelli@istitutotumori.mi.it.
authors: Roberto
authors: R
authors: Iacovelli
authors: Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: ilaria.bossi@istitutotumori.mi.it.
authors: Ilaria
authors: I
authors: Bossi
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: lo.ve@tiscali.it.
authors: Veronica
authors: V
authors: Lonati
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: mara.ghily@alice.it.
authors: Mara
authors: M
authors: Ghilardi
authors: Department of Medical Oncology, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Electronic address: filippo.debraud@istitutotumori.mi.it.
authors: Filippo
authors: F
authors: de Braud
authors: Department of Oncology, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Electronic address: sandro.barni@ospedale.treviglio.bg.it.
authors: Sandro
authors: S
authors: Barni
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D016017:Odds Ratio; D000077544:Panitumumab; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab
keywords: BRAF mutation; Cetuximab; Colorectal cancer; Meta-analysis; Panitumumab