Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial | Cancer Biomarkers | JAMA Oncology | JAMA Network
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Original Investigation
May 2015

Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial

Author Affiliations
  • 1Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain
  • 2Laboratory of Molecular Biology, Pangaea Biotech, Barcelona, Spain
  • 3Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain
  • 4Service de Pathologie Respiratoire et d’Allergologie, Hôpital du Cluzeau, Limoges, France
  • 5Medical Oncology Service, Catalan Institute of Oncology, Hospital Duran i Reynals, L’Hospitalet, Spain
  • 6Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  • 7Medical Oncology Service, Hospital General de Alicante, Alicante, Spain
  • 8Medical Oncology Service, Hospital 12 de Octubre, Madrid, Spain
  • 9Medical Oncology Service, Catalan Institute of Oncology, Hospital Dr Josep Trueta, Girona, Spain
  • 10Medical Oncology Service, Hospital La Paz, Madrid, Spain
  • 11Medical Oncology Service, Hospital Vall d’Hebron, Barcelona, Spain
  • 12Medical Oncology Service, Hospital Son Llatzer, Palma de Mallorca, Spain
  • 13Medical Oncology Service, Hospital Clínic de Valencia, Valencia, Spain
  • 14Medical Oncology Service, Hospital Clínic, Barcelona, Spain
  • 15Medical Oncology Service, Hospital Lozano Blesa, Zaragoza, Spain
  • 16Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
  • 17European Institute of Oncology, Milan, Italy
  • 18Medical Oncology Service, Centre François Baclesse, Caen, France
  • 19CHU Rennes Hopital Ponchaillou, Rennes, France
  • 20Medical Oncology Service, Hospital Universitario Virgen del Rocío, Sevilla, Spain
  • 21Pivotal, Madrid, Spain
  • 22MORe Foundation, Barcelona, Spain
  • 23Cancer Therapeutic Innovation Group, New York, New York
JAMA Oncol. 2015;1(2):149-157. doi:10.1001/jamaoncol.2014.257
Abstract

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00446225

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