Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations
- Rafael Rosell1,3,
- Miguel Angel Molina3,
- Carlota Costa3,
- Sara Simonetti3,
- Ana Gimenez-Capitan3,
- Jordi Bertran-Alamillo3,
- Clara Mayo3,
- Teresa Moran1,
- Pedro Mendez1,
- Felipe Cardenal6,
- Dolores Isla7,
- Mariano Provencio8,
- Manuel Cobo11,
- Amelia Insa12,
- Rosario Garcia-Campelo13,
- Noemi Reguart4,
- Margarita Majem5,
- Santiago Viteri3,
- Enric Carcereny1,
- Ruth Porta14,
- Bartomeu Massuti15,
- Cristina Queralt1,
- Itziar de Aguirre1,
- Jose Miguel Sanchez9,
- Maria Sanchez-Ronco16,
- Jose Luis Mate2,
- Aurelio Ariza2,
- Susana Benlloch3,
- Jose Javier Sanchez10,
- Trever G Bivona17,
- Charles L Sawyers17,18, and
- Miquel Taron1,3
- 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:
Rafael Rosell, Catalan Institute of Oncology, Medical Oncology Service, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, Badalona 08916, Spain. Phone: 34-93-497-89-25; Fax: 34-93-497-89-50. E-mail: rrosell{at}iconcologia.net
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. Clin Cancer Res; 17(5); 1–9. ©2011 AACR.
This article is featured in Highlights of This Issue, p. 947
Footnotes
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Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
- Received August 11, 2010.
- Revision received October 27, 2010.
- Accepted November 25, 2010.
- ©2011 American Association for Cancer Research.
