Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

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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

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Most cited references 27

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EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

W Pao, V. Miller, M Zakowski … (2004)

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

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The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer.

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First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

Lecia V. Sequist, Renato G. Martins, David Spigel … (2008)

Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms. Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification. First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2009

Publication date (Electronic): 5 May 2009

Volume: 4

Issue: 5

Electronic Location Identifier: e5133

Affiliations

[1 ]Catalan Institute of Oncology, Badalona, Spain

[2 ]Pangaea Biotech, USP Institut Universitari Dexeus, Barcelona, Spain

[3 ]Autonomous University of Madrid, Madrid, Spain

[4 ]Hospital Clinico Carlos Haya, Malaga, Spain

[5 ]Hospital Puerta de Hierro, Madrid, Spain

[6 ]Fundación Jimenez Diaz, Madrid, Spain

[7 ]Hospital Basurto, Bilbao, Spain

[8 ]Hospital de la Princesa, Madrid, Spain

[9 ]Complejo Hospitalario de Leon, Leon, Spain

[10 ]Hospital Reina Sofia, Cordoba, Spain

[11 ]Hospital Morales Meseguer, Murcia, Spain

[12 ]Hospital Provincial de Castellon, Castellon, Spain

[13 ]Althaia, Manresa, Spain

[14 ]Hospital Clinico Lozano Blesa, Zaragoza, Spain

[15 ]Hospital de Alcorcon, Madrid, Spain

[16 ]Hospital Municipal de Badalona, Badalona, Spain

[17 ]Hospital de Cruces, Barakaldo, Spain

[18 ]Hospital Universitario de Canarias, Tenerife, Spain

[19 ]Hospital Clinic, Barcelona, Spain

[20 ]Hospital de Terrassa, Barcelona, Spain

Ordway Research Institute, United States of America

Author notes

* E-mail: rrosell@ 123456ico.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

Article

Publisher ID: 08-PONE-RA-07549R1

DOI: 10.1371/journal.pone.0005133

PMC ID: 2673583

PubMed ID: 19415121

SO-VID: 3bb027b2-2dc7-48dc-be46-9052f76874fe

Copyright © Rosell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 December 2008

Date accepted : 3 March 2009

Page count

Pages: 9

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Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

Trial Registration

Related collections

PLOS Climate

Most cited references 27

EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

The DNA damage response: ten years after.

First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

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Contributors

Journal

Affiliations

Author notes

Article

History

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Comments

Comment on this article

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Cited by 32

Most referenced authors 1,273