Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial
Open accessAbstract
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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A growing body of evidence shows many clinical uses for ctDNA in adults with solid tumors, from prognostication and minimal residual disease evaluation to detection of targetable alterations.
“There is a growing body of data demonstrating numerous clinical applications for ctDNA in adults with solid tumors, ranging from prognostication and evaluation of minimal residual disease (MRD) to detection of targetable alterations.7–12”
From Clinical Liquid Biopsy Testing for Detection of Actionable Genomic Alterations in Children and Young Adults With Advanced Solid Tumors on the GAIN Study (2026) · cites this paper as [9]
In the EURTAC trial, baseline cfDNA was detected in 78% of patients (76 of 97), and the presence of L858R mutation in cfDNA was suggested to be a negative prognostic factor.
“In the EURTAC trial, a peptide nucleic acid-mediated 5 0 -nuclease real-time polymerase chain reaction (PCR) assay was used to detect cfDNA at baseline in 78% of patients (76 of 97), which suggested that the presence of L858R mutation in cfDNA is a negative prognostic factor.53”
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- Authors
- Karachaliou, N., Mayo-de las Casas, C., Queralt, C., de Aguirre, I., Melloni, B., Cardenal, F., Garcia-Gomez, R., Massuti, B., Sánchez, J. M., Porta, R., Ponce-Aix, S., Moran, T., Carcereny, E., Felip, E., Bover, I., Insa, A., Reguart, N., Isla, D., Vergnenegre, A., de Marinis, F., Gervais, R., Corre, R., Paz-Ares, L., Morales-Espinosa, D., Viteri, S., Drozdowskyj, A., Jordana-Ariza, N., Ramirez-Serrano, J. L., Molina-Vila, M. A., & Rosell, R.
- Affiliations
- Instituto Oncológico Dr. Rosell (ES)
- Laboratory of Molecular Biology, Pangaea Biotech, Barcelona, Spain
- Institut Català d'Oncologia (ES)
- Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain
- Centre Hospitalier Universitaire de Limoges (FR)
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Medical Oncology Service, Hospital General de Alicante, Alicante, Spain
- Hospital Universitario 12 De Octubre (ES)
- Hospital Universitario La Paz (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Son Llatzer (ES)
- Hospital Clínico Universitario de Valencia (ES)
- Medical Oncology Service, Hospital Clínic, Barcelona, Spain
- Hospital Clínico Universitario Lozano Blesa (ES)
- Service de Pathologie Respiratoire et d’Allergologie, Hôpital du Cluzeau, Limoges, France
- Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy17European Institute of Oncology, Milan, Italy
- Centre François Baclesse (FR)
- Hôpital Pontchaillou (FR)
- Hospital Universitario Virgen del Rocío (ES)
- Pivotal (Spain) (ES)
- Corresponding author
- Rosell, Rafael
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-05-01
- Volume
- 1
- Issue
- 2
- Pages
- 149
- ISSN
- 2374-2437 (ISSN-L)
- OpenAlex
- W2013768132
- Cited by
- 239
- References
- 9
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 17 · 2020: 24 · 2019: 22 · 2018: 42 · 2017: 44 · 2016: 40 · 2015: 9
- FWCI
- 35.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Oncology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- L858R mutation, cell-free DNA, liquid biopsy, non-small cell lung cancer, erlotinib, exon 19 deletion, overall survival, progression-free survival, predictive biomarkers, first-line therapy, chemotherapy comparison, treatment response, prognostic factors, EGFR tyrosine kinase inhibitors
- MeSH terms
- Erlotinib Hydrochloride, Aged, Antineoplastic Agents, DNA Mutational Analysis, Exons, Feasibility Studies, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Predictive Value of Tests, Risk Factors, Time Factors, Biomarkers, Tumor, Multivariate Analysis, Chi-Square Distribution, Proportional Hazards Models, Treatment Outcome, Disease Progression, Disease-Free Survival, Protein Kinase Inhibitors, Kaplan-Meier Estimate, Real-Time Polymerase Chain Reaction, ErbB Receptors
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