title: Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial.
abstract: OBJECTIVE
  The EURTAC trial demonstrated the greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic epidermal growth factor receptor (EGFR) mutations (exon 19 deletion or L858R mutation in exon 21) in tumor tissue.
  
  
  OBJECTIVE
  To assess the feasibility of using circulating free DNA (cfDNA) from blood samples as a surrogate for tumor biopsy for determining EGFR mutation status and to correlate EGFR mutations in cfDNA with outcome.
  
  
  METHODS
  This prespecified analysis was a secondary objective of the EURTAC trial using patients included in the EURTAC trial from 2007 to 2011 with available baseline serum or plasma samples. Patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, and no prior chemotherapy for metastatic disease and were treated with erlotinib or chemotherapy. EGFR mutations were examined in cfDNA isolated from 97 baseline blood samples by our novel peptide nucleic acid-mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay.
  
  
  METHODS
  Overall survival (OS), progression-free survival (PFS), and response to therapy were correlated with type of EGFR mutations in cfDNA.
  
  
  RESULTS
  In samples from 76 of 97 (78%) patients with usable blood samples, EGFR mutations in cfDNA were detected. Median OS was shorter in patients with the L858R mutation in cfDNA than in those with the exon 19 deletion (13.7 [95% CI, 7.1-17.7] vs 30.0 [95% CI, 19.3-37.7] months; P < .001). Univariate analyses of patients with EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter OS (hazard ratio [HR], 2.70 [95% CI, 1.60-4.56]; P < .001) and PFS (HR, 2.04 [95% CI, 1.20-3.48]; P = .008). For patients with the L858R mutation in tissue, median OS was 13.7 (95% CI, 7.1-17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1-46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09-4.52]; P = .03). In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer PFS (HR, 0.41 [95% CI, 0.23-0.74]; P = .003).
  
  
  CONCLUSIONS
  The peptide nucleic acid-mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay used in this study can be used to efficiently assess EGFR mutations in cfDNA. The L858R mutation in cfDNA may be a novel surrogate prognostic marker.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00446225.
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: Niki
authors.initials: N
authors.lastname: Karachaliou
authors.affiliation: Laboratory of Molecular Biology, Pangaea Biotech, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Mayo-de las Casas
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Queralt
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: de Aguirre
authors.affiliation: Service de Pathologie Respiratoire et d'Allergologie, Hôpital du Cluzeau, Limoges, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Melloni
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology, Hospital Duran i Reynals, L'Hospitalet, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cardenal
authors.affiliation: Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Garcia-Gomez
authors.affiliation: Medical Oncology Service, Hospital General de Alicante, Alicante, Spain.
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Massuti
authors.affiliation: Medical Oncology Service, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Sánchez
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology, Hospital Dr Josep Trueta, Girona, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Porta
authors.affiliation: Medical Oncology Service, Hospital La Paz, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ponce-Aix
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Carcereny
authors.affiliation: Medical Oncology Service, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.affiliation: Medical Oncology Service, Hospital Son Llatzer, Palma de Mallorca, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Bover
authors.affiliation: Medical Oncology Service, Hospital Clínic de Valencia, Valencia, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Insa
authors.affiliation: Medical Oncology Service, Hospital Clínic, Barcelona, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Reguart
authors.affiliation: Medical Oncology Service, Hospital Lozano Blesa, Zaragoza, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Isla
authors.affiliation: Service de Pathologie Respiratoire et d'Allergologie, Hôpital du Cluzeau, Limoges, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vergnenegre
authors.affiliation: Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy17European Institute of Oncology, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Marinis
authors.affiliation: Medical Oncology Service, Centre François Baclesse, Caen, France.
authors.forename: Radj
authors.initials: R
authors.lastname: Gervais
authors.affiliation: CHU Rennes Hopital Ponchaillou, Rennes, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Corre
authors.affiliation: Medical Oncology Service, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Morales-Espinosa
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.affiliation: Pivotal, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Drozdowskyj
authors.affiliation: Laboratory of Molecular Biology, Pangaea Biotech, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Jordana-Ariza
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ramirez-Serrano
authors.affiliation: Laboratory of Molecular Biology, Pangaea Biotech, Barcelona, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Molina-Vila
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain3Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain22MORe Foundation, Barcelona, Spain23Cancer Therapeutic Innovation Group, New York, New York.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D005091:Exons; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors