title: Optimizing single agent panitumumab therapy in pre-treated advanced colorectal cancer.
abstract: OBJECTIVE
  To improve the selection of advanced colorectal cancer patients to panitumumab by optimizing the assessment of RAS (KRAS-NRAS) mutations.
  
  
  METHODS
  Using a centralized pyrosequencing RAS assay, we analyzed the tumors of 94 patients, wild-type for KRAS mutations (codons 12 to 13) by Sanger sequencing (SS), treated with panitumumab.
  
  
  RESULTS
  By SS analysis, 94 (62%) of 152 patients were wild-type and their objective response rate to panitumumab was 17%. We first optimized the KRAS test, by performing an accurate tissue-dissection step followed by pyrosequencing, a more sensitive method, and found further mutations in 12 (12.8%) cases. Secondly, tumors were subjected to RAS extension analysis (KRAS, exons 3 to 4; NRAS exons 2 to 4) by pyrosequencing that allowed to identify several rare mutations: KRAS codon 61, 5.3%; codon 146, 5.3%; NRAS, 9.5%. Overall, RAS mutation rate was 32.9%. All patients with additional RAS mutations had progressive or stable disease, except 3 patients with mutations at codon 61 of KRAS or NRAS who experienced partial (2 cases) or complete response. By excluding from the analysis 11 cases with mutations at codons 61, no patient was responsive to treatment (P=.021). RAS wild-type versus RAS mutated cases had a significantly better time to progression (P=.044), that resulted improved (p=.004) by excluding codon 61 mutations.
  
  
  CONCLUSIONS
  This study shows that by optimizing the RAS test it is possible to significantly improve the identification of patients who do not gain benefit of panitumumab. Prospective studies are warranted to determine the clinical significance of rare mutations.
authors.affiliation: Department of Oncology, San Filippo Neri Hospital, Rome, Italy. Electronic address: gasparini.oncology@hotmail.it.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Gasparini
authors.affiliation: Center of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, Italy.
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
authors.affiliation: Department of Oncology, San Filippo Neri Hospital, Rome, Italy.
authors.forename: Mario Rosario
authors.initials: MR
authors.lastname: D'Andrea
authors.affiliation: Oncology Unit Santa Maria degli Angeli, Pordenone, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Tumolo
authors.affiliation: Oncology Unit B IRCCS Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Buonadonna
authors.affiliation: Oncology Unit Ospedale Villa San Pietro Fatebenefratelli, Rome, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Pavese
authors.affiliation: Oncology Unit Ospedale Garibaldi, Catania, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cordio
authors.affiliation: Oncology Unit Department of Clinical and Experimental Science, University of Chieti, Chieti, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: De Tursi
authors.affiliation: Oncology Unit Ospedali Riuniti di Bergamo, Bergamo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mosconi
authors.affiliation: Department of Oncology, San Filippo Neri Hospital, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Stumbo
authors.affiliation: Center of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.affiliation: Center of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003062:Codon; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000077544:Panitumumab; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D003062:Codon; D000077544:Panitumumab