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MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial
INTRODUCTION: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. METHODS: We used immunohistochemistry (IHC) t...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354834/ https://www.ncbi.nlm.nih.gov/pubmed/28008145 http://dx.doi.org/10.18632/oncotarget.14025 |
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author | Levallet, Guénaëlle Dubois, Fatéméh Fouret, Pierre Antoine, Martine Brosseau, Solenn Bergot, Emmanuel Beau-Faller, Michèle Gounant, Valérie Brambilla, Elisabeth Debieuvre, Didier Molinier, Olivier Galateau-Sallé, Françoise Mazieres, Julien Quoix, Elisabeth Pujol, Jean-Louis Moro-Sibilot, Denis Langlais, Alexandra Morin, Franck Westeel, Virginie Zalcman, Gérard |
author_facet | Levallet, Guénaëlle Dubois, Fatéméh Fouret, Pierre Antoine, Martine Brosseau, Solenn Bergot, Emmanuel Beau-Faller, Michèle Gounant, Valérie Brambilla, Elisabeth Debieuvre, Didier Molinier, Olivier Galateau-Sallé, Françoise Mazieres, Julien Quoix, Elisabeth Pujol, Jean-Louis Moro-Sibilot, Denis Langlais, Alexandra Morin, Franck Westeel, Virginie Zalcman, Gérard |
author_sort | Levallet, Guénaëlle |
collection | PubMed |
description | INTRODUCTION: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. METHODS: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens. RESULTS: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death. INTERPRETATION: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors. |
format | Online Article Text |
id | pubmed-5354834 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53548342017-04-24 MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial Levallet, Guénaëlle Dubois, Fatéméh Fouret, Pierre Antoine, Martine Brosseau, Solenn Bergot, Emmanuel Beau-Faller, Michèle Gounant, Valérie Brambilla, Elisabeth Debieuvre, Didier Molinier, Olivier Galateau-Sallé, Françoise Mazieres, Julien Quoix, Elisabeth Pujol, Jean-Louis Moro-Sibilot, Denis Langlais, Alexandra Morin, Franck Westeel, Virginie Zalcman, Gérard Oncotarget Research Paper INTRODUCTION: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. METHODS: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens. RESULTS: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death. INTERPRETATION: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors. Impact Journals LLC 2016-12-19 /pmc/articles/PMC5354834/ /pubmed/28008145 http://dx.doi.org/10.18632/oncotarget.14025 Text en Copyright: © 2017 Levallet et al. http://creativecommons.org/licenses/by/3.0/ 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. |
spellingShingle | Research Paper Levallet, Guénaëlle Dubois, Fatéméh Fouret, Pierre Antoine, Martine Brosseau, Solenn Bergot, Emmanuel Beau-Faller, Michèle Gounant, Valérie Brambilla, Elisabeth Debieuvre, Didier Molinier, Olivier Galateau-Sallé, Françoise Mazieres, Julien Quoix, Elisabeth Pujol, Jean-Louis Moro-Sibilot, Denis Langlais, Alexandra Morin, Franck Westeel, Virginie Zalcman, Gérard MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
title | MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
title_full | MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
title_fullStr | MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
title_full_unstemmed | MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
title_short | MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early–stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
title_sort | msh2/brca1 expression as a dna-repair signature predicting survival in early–stage lung cancer patients from the ifct-0002 phase 3 trial |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354834/ https://www.ncbi.nlm.nih.gov/pubmed/28008145 http://dx.doi.org/10.18632/oncotarget.14025 |
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