Niki Karachaliou1, Clara Mayo-de las Casas2, Cristina Queralt3, Itziar de Aguirre3, Boris Melloni4, Felipe Cardenal5, Ramon Garcia-Gomez6, Bartomeu Massuti7, José Miguel Sánchez8, Ruth Porta9, Santiago Ponce-Aix10, Teresa Moran3, Enric Carcereny3, Enriqueta Felip11, Isabel Bover12, Amelia Insa13, Noemí Reguart14, Dolores Isla15, Alain Vergnenegre4, Filippo de Marinis16, Radj Gervais17, Romain Corre18, Luis Paz-Ares19, Daniela Morales-Espinosa1, Santiago Viteri1, Ana Drozdowskyj20, Núria Jordana-Ariza2, Jose Luis Ramirez-Serrano3, Miguel Angel Molina-Vila2, Rafael Rosell21. 1. Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain. 2. Laboratory of Molecular Biology, Pangaea Biotech, Barcelona, Spain. 3. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain. 4. Service de Pathologie Respiratoire et d'Allergologie, Hôpital du Cluzeau, Limoges, France. 5. Medical Oncology Service, Catalan Institute of Oncology, Hospital Duran i Reynals, L'Hospitalet, Spain. 6. Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 7. Medical Oncology Service, Hospital General de Alicante, Alicante, Spain. 8. Medical Oncology Service, Hospital 12 de Octubre, Madrid, Spain. 9. Medical Oncology Service, Catalan Institute of Oncology, Hospital Dr Josep Trueta, Girona, Spain. 10. Medical Oncology Service, Hospital La Paz, Madrid, Spain. 11. Medical Oncology Service, Hospital Vall d'Hebron, Barcelona, Spain. 12. Medical Oncology Service, Hospital Son Llatzer, Palma de Mallorca, Spain. 13. Medical Oncology Service, Hospital Clínic de Valencia, Valencia, Spain. 14. Medical Oncology Service, Hospital Clínic, Barcelona, Spain. 15. Medical Oncology Service, Hospital Lozano Blesa, Zaragoza, Spain. 16. Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy17European Institute of Oncology, Milan, Italy. 17. Medical Oncology Service, Centre François Baclesse, Caen, France. 18. CHU Rennes Hopital Ponchaillou, Rennes, France. 19. Medical Oncology Service, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 20. Pivotal, Madrid, Spain. 21. 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.
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 witherlotinib 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.
RCT Entities:
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.
Authors: Adrian G Sacher; Cloud Paweletz; Suzanne E Dahlberg; Ryan S Alden; Allison O'Connell; Nora Feeney; Stacy L Mach; Pasi A Jänne; Geoffrey R Oxnard Journal: JAMA Oncol Date: 2016-08-01 Impact factor: 31.777
Authors: Lee S Schwartzberg; Hidehito Horinouchi; David Chan; Sara Chernilo; Michaela L Tsai; Dolores Isla; Carles Escriu; John P Bennett; Kim Clark-Langone; Christer Svedman; Pascale Tomasini Journal: NPJ Precis Oncol Date: 2020-06-24
Authors: Stepan M Esagian; Georgia Ι Grigoriadou; Ilias P Nikas; Vasileios Boikou; Peter M Sadow; Jae-Kyung Won; Konstantinos P Economopoulos Journal: J Cancer Res Clin Oncol Date: 2020-05-27 Impact factor: 4.553