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Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations
Open accessPublished version of a preprint
Abstract
PURPOSE: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. EXPERIMENTAL DESIGN: We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined. RESULTS: The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival. CONCLUSIONS: Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression.
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“This suggests, but does not prove, that it pre-exists in a small fraction of cells, and that those cells are selected for during the course of treatment (Maheswaran et al., 2008; Rosell et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Rosell et al., 2011
In the citing paper
“Recent studies suggest that highly sensitive methods can detect the T790M mutation in ~35% of pre-treatment biopsies.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Rosell et al., 2011
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Metadata
- Authors
- Rosell, R., Molina, M. A., Costa, C., Simonetti, S., Gimenez-Capitan, A., Bertran-Alamillo, J., Mayo, C., Moran, T., Mendez, P., Cardenal, F., Isla, D., Provencio, M., Cobo, M., Insa, A., Garcia-Campelo, R., Reguart, N., Majem, M., Viteri, S., Carcereny, E., Porta, R., Massuti, B., Queralt, C., de Aguirre, I., Sanchez, J. M., Sanchez-Ronco, M., Mate, J. L., Ariza, A., Benlloch, S., Sanchez, J. J., Bivona, T. G., Sawyers, C. L., & Taron, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Authors' Affiliations: 1Catalan Institute of Oncology, Hospital Germans Trias i Pujol; 2Hospital Germans Trias i Pujol, Badalona, Spain; 3USP Dexeus University Institute, Pangaea Biotech; 4Hospital Clinic; and 5Hospital Sant Pau, Barcelona, Spain; 6Catalan Institute of Oncology, Hospital Duran i Reynals, Bellvitge, Spain; 7Hospital Lozano Blesa, Zaragoza, Spain; 8Hospital Puerta de Hierro; 9MD Anderson; and 10Autonomous University of Madrid, Madrid, Spain; 11Hospital Carlos Haya, Malaga, Spain; 12Hospital Clinico Universitario, Valencia, Spain; 13Hospital Juan Canalejo, La Coruña, Spain; 14Catalan Institute of Oncology, Hospital Josep Trueta, Girona, Spain; 15Hospital General, Alicante, Spain; 16University of Alcala de Henares, Alcala de Henares, Spain; 17Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York; and 18Howard Hughes Medical Institute, Chevy Chase, Maryland
- Corresponding author
- Rosell, Rafael
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2011-03-01
- Volume
- 17
- Issue
- 5
- Pages
- 1160-1168
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2156560090
- Cited by
- 304
- References
- 48
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 11 · 2019: 20 · 2018: 20 · 2017: 34 · 2016: 31 · 2015: 33 · 2014: 37 · 2013: 47 · 2012: 23
- FWCI
- 33.19
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- T790M mutation, BRCA1 mRNA expression, erlotinib, advanced non-small cell lung cancer, EGFR mutation, exon 19 deletion, L858R mutation, progression-free survival, DNA repair pathways, predictive biomarkers, personalized treatment
- MeSH terms
- Erlotinib Hydrochloride, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA Repair, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, RNA, Messenger, Biomarkers, Tumor, Gene Expression, Treatment Outcome, Disease-Free Survival, Genes, erbB-1, BRCA1 Protein, Genes, BRCA1, Receptor Protein-Tyrosine Kinases, Protein Kinase Inhibitors, ErbB Receptors
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