title: Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial.
abstract: BACKGROUND
  Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information.
  
  
  METHODS
  In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer.
  
  
  RESULTS
  Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect.
  
  
  CONCLUSIONS
  This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.
authors.affiliation: Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples. Electronic address: fortunato.ciardiello@unina2.it.
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Naples.
authors.forename: N
authors.initials: N
authors.lastname: Normanno
authors.affiliation: Medical Oncology, Hospital Casa Sollievo Della Sofferenza-San Giovanni Rotondo (Foggia), San Giovanni Rotondo.
authors.forename: E
authors.initials: E
authors.lastname: Maiello
authors.affiliation: Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples.
authors.forename: E
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples.
authors.forename: T
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Department of Medical Oncology, Hospital SS. Annunziata, Taranto.
authors.forename: S
authors.initials: S
authors.lastname: Pisconti
authors.affiliation: Department of Medical Oncology, National Cancer Institute Giovanni Paolo II, Bari.
authors.forename: F
authors.initials: F
authors.lastname: Giuliani
authors.affiliation: Department of Medical Oncology, University Hospital A. Gemelli, Rome.
authors.forename: C
authors.initials: C
authors.lastname: Barone
authors.affiliation: Department of Medical Oncology, Hospital 'A. Cardarelli', Naples.
authors.forename: G
authors.initials: G
authors.lastname: Cartenì
authors.affiliation: Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Naples.
authors.forename: A M
authors.initials: AM
authors.lastname: Rachiglio
authors.affiliation: Department of Medical Oncology, Hospital Monaldi- Azienda Ospedaliera dei Colli, Napoles.
authors.forename: V
authors.initials: V
authors.lastname: Montesarchio
authors.affiliation: Department of Medical Oncology, Univeristy Hospital Campus Bio-Medico di Rome, Rome.
authors.forename: G
authors.initials: G
authors.lastname: Tonini
authors.affiliation: Department of Medical Oncology, National Cancer Institute Giovanni Paolo II, Bari.
authors.forename: D
authors.initials: D
authors.lastname: Rizzi
authors.affiliation: Department of Medical Oncology, Hospital A. Perrino, Brindisi.
authors.forename: S
authors.initials: S
authors.lastname: Cinieri
authors.affiliation: Department of Medical Oncology, Hospital Garibaldi, Nesima, Catania.
authors.forename: R
authors.initials: R
authors.lastname: Bordonaro
authors.affiliation: Department of Medical Oncology, Hospital Sacro Cuore di Gesù, Fatebenefratelli, Benevento.
authors.forename: A
authors.initials: A
authors.lastname: Febbraro
authors.affiliation: Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples.
authors.forename: F
authors.initials: F
authors.lastname: De Vita
authors.affiliation: Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples.
authors.forename: M
authors.initials: M
authors.lastname: Orditura
authors.affiliation: Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Naples.
authors.forename: F
authors.initials: F
authors.lastname: Fenizia
authors.affiliation: Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Naples.
authors.forename: M
authors.initials: M
authors.lastname: Lambiase
authors.affiliation: Department of Medical Oncology, Hospital Polo Occidentale, Castellaneta, Bari.
authors.forename: A
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Naples.
authors.forename: F
authors.initials: F
authors.lastname: Tatangelo
authors.affiliation: Department of Pathology, National Cancer Institute 'Fondazione Giovanni Pascale', Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Botti
authors.affiliation: Department of Medical Oncology, National Cancer Institute Giovanni Paolo II, Bari.
authors.forename: G
authors.initials: G
authors.lastname: Colucci
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D005472:Fluorouracil / Q000627:therapeutic use; D020558:GTP Phosphohydrolases / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: BRAF; KSA/NRAS; PIK3CA; cetuximab; colorectal cancer; next-generation sequencing