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PLoS ONE. 2009; 4(5): e5133.
Published online 2009 May 5. doi: 10.1371/journal.pone.0005133.
PMCID: PMC2673583
Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression
Rafael Rosell,1,2* Laia Perez-Roca,1 Jose Javier Sanchez,3 Manuel Cobo,4 Teresa Moran,1 Imane Chaib,1 Mariano Provencio,5 Manuel Domine,6 Maria Angeles Sala,7 Ulpiano Jimenez,8 Pilar Diz,9 Isidoro Barneto,10 Jose Antonio Macias,11 Ramon de las Peñas,12 Silvia Catot,13 Dolores Isla,14 Jose Miguel Sanchez,15¤ Rafael Ibeas,16 Guillermo Lopez-Vivanco,17 Juana Oramas,18 Pedro Mendez,1 Noemi Reguart,19 Remei Blanco,20 and Miquel Taron1,2
1Catalan Institute of Oncology, Badalona, Spain
2Pangaea Biotech, USP Institut Universitari Dexeus, Barcelona, Spain
3Autonomous University of Madrid, Madrid, Spain
4Hospital Clinico Carlos Haya, Malaga, Spain
5Hospital Puerta de Hierro, Madrid, Spain
6Fundación Jimenez Diaz, Madrid, Spain
7Hospital Basurto, Bilbao, Spain
8Hospital de la Princesa, Madrid, Spain
9Complejo Hospitalario de Leon, Leon, Spain
10Hospital Reina Sofia, Cordoba, Spain
11Hospital Morales Meseguer, Murcia, Spain
12Hospital Provincial de Castellon, Castellon, Spain
13Althaia, Manresa, Spain
14Hospital Clinico Lozano Blesa, Zaragoza, Spain
15Hospital de Alcorcon, Madrid, Spain
16Hospital Municipal de Badalona, Badalona, Spain
17Hospital de Cruces, Barakaldo, Spain
18Hospital Universitario de Canarias, Tenerife, Spain
19Hospital Clinic, Barcelona, Spain
20Hospital de Terrassa, Barcelona, Spain
Mikhail V. Blagosklonny, Editor
Ordway Research Institute, United States of America
* E-mail: rrosell/at/ico.scs.es
Conceived and designed the experiments: RR. Performed the experiments: LPR IC PM. Analyzed the data: JJS. Wrote the paper: RR JJS MT. Included patients in the trial. Included patients in the trial: MC TM MP MD MAS UJ PD IB JAM RdlP SC DI JMS RI GLV JO NR. Supervised the laboratory work: MT.
¤Current address: Hospital 12 de Octubre, Madrid, Spain
Received December 1, 2008; Accepted March 3, 2009.
Abstract
Background
Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.
Methodology/Principal Findings
We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1–1.7]; P = 0.05).
Conclusions/Significance
Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.
Trial Registration
ClinicalTrials.gov NCT00883480