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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

Guénaëlle Levallet, Fatéméh Dubois, Pierre Fouret, Martine Antoine, Solenn Brosseau, Emmanuel Bergot, Michèle Beau-Faller, Valérie Gounant, Elisabeth Brambilla, Didier Debieuvre, Olivier Molinier, Françoise Galateau-Sallé, Julien Mazieres, Elisabeth Quoix, Jean-Louis Pujol, Denis Moro-Sibilot, Alexandra Langlais, Franck Morin, Virginie Westeel and Gérard Zalcman _

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Oncotarget. 2017; 8:4313-4329. https://doi.org/10.18632/oncotarget.14025

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Abstract

Guénaëlle Levallet1, Fatéméh Dubois2, Pierre Fouret3, Martine Antoine4, Solenn Brosseau2,5,6, Emmanuel Bergot2,5, Michèle Beau-Faller7, Valérie Gounant6,8, Elisabeth Brambilla9, Didier Debieuvre10, Olivier Molinier11, Françoise Galateau-Sallé1, Julien Mazieres12, Elisabeth Quoix13, Jean-Louis Pujol14, Denis Moro-Sibilot15, Alexandra Langlais16, Franck Morin16, Virginie Westeel17 and Gérard Zalcman5,6,18,19

1 Service d’Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, France

2 Normandie Université; UMR 1086 INSERM, Caen, France

3 Service d’Anatomie Pathologique, Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie (UPMC), Paris, France

4 Service d’Anatomie Pathologique, Hôpital Tenon, AP-HP, Université Pierre et Marie Curie (UPMC), Paris, France

5 Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, cedex, France

6 Service d’Oncologie Thoracique, Hôpital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France

7 Laboratoire de Biochimie et Biologie moléculaire, Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Université de Strasbourg, BP426 Strasbourg, Cedex, France

8 Service de Pneumologie, Hôpital Tenon, AP-HP, Université Pierre et Marie Curie (UPMC), Paris, France

9 Service d’Anatomie Pathologique, Hôpital Albert Michallon, Centre Hospitalier Universitaire de Grenoble, La Tronche, France

10 Service de Pneumologie, GHRMSA-Centre Hospitalier Eric Müller, Mulhouse, France

11 Service de Pneumologie, Centre Hospitalier du Mans, Le Mans, France

12 Service de Pneumologie, Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse III, Toulouse, France

13 Service de Pneumologie, Nouvel Hôpital Civil, Hospices Civils de Strasbourg, Université de Strasbourg, BP426 Strasbourg, Cedex, France

14 Service de Pneumologie, Centre Hospitalier Universitaire Arnaud de Villeneuve, Université de Montpellier, Montpellier, France

15 Unité d’Oncologie Thoracique–Pneumologie, CHU de Grenoble, INSERM U823, Grenoble, France

16 Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France

17 Service de Pneumologie, Hôpital Jean-Minjoz, Centre Hospitalier Universitaire de Besançon, Université de Franche-Comté, Besançon, France

18 CIC INSERM 1425-CLIP2 Paris-Nord, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France

19 On Behalf of the IFCT (Intergroupe Francophone de Cancérologie Thoracique)

Correspondence to:

Gérard Zalcman, email:

Keywords: non-small cell lung cancer; neo-adjuvant chemotherapy; MSH2; BRCA1; MGMT

Received: August 08, 2016 Accepted: December 05, 2016 Published: December 19, 2016

Abstract

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.


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