title: MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service d'Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, France.
authors.forename: Guénaëlle
authors.initials: G
authors.lastname: Levallet
authors.affiliation: Normandie Université; UMR 1086 INSERM, Caen, France.
authors.forename: Fatéméh
authors.initials: F
authors.lastname: Dubois
authors.affiliation: Service d'Anatomie Pathologique, Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
authors.affiliation: Service d'Anatomie Pathologique, Hôpital Tenon, AP-HP, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Antoine
authors.affiliation: Normandie Université; UMR 1086 INSERM, Caen, France.|Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, cedex, France.|Service d'Oncologie Thoracique, Hôpital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France.
authors.forename: Solenn
authors.initials: S
authors.lastname: Brosseau
authors.affiliation: Normandie Université; UMR 1086 INSERM, Caen, France.|Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, cedex, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bergot
authors.affiliation: Laboratoire de Biochimie et Biologie moléculaire, Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Université de Strasbourg, BP426 Strasbourg, Cedex, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.affiliation: Service d'Oncologie Thoracique, Hôpital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France.|Service de Pneumologie, Hôpital Tenon, AP-HP, Université Pierre et Marie Curie (UPMC), Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gounant
authors.affiliation: Service d'Anatomie Pathologique, Hôpital Albert Michallon, Centre Hospitalier Universitaire de Grenoble, La Tronche, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Service de Pneumologie, GHRMSA-Centre Hospitalier Eric Müller, Mulhouse, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Debieuvre
authors.affiliation: Service de Pneumologie, Centre Hospitalier du Mans, Le Mans, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Molinier
authors.affiliation: Service d'Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Galateau-Sallé
authors.affiliation: Service de Pneumologie, Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse III, Toulouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Service de Pneumologie, Nouvel Hôpital Civil, Hospices Civils de Strasbourg, Université de Strasbourg, BP426 Strasbourg, Cedex, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Quoix
authors.affiliation: Service de Pneumologie, Centre Hospitalier Universitaire Arnaud de Villeneuve, Université de Montpellier, Montpellier, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pujol
authors.affiliation: Unité d'Oncologie Thoracique-Pneumologie, CHU de Grenoble, INSERM U823, Grenoble, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Langlais
authors.affiliation: Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morin
authors.affiliation: Service de Pneumologie, Hôpital Jean-Minjoz, Centre Hospitalier Universitaire de Besançon, Université de Franche-Comté, Besançon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Westeel
authors.affiliation: Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Université, Caen, cedex, France.|Service d'Oncologie Thoracique, Hôpital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France.|CIC INSERM 1425-CLIP2 Paris-Nord, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.|On Behalf of the IFCT (Intergroupe Francophone de Cancérologie Thoracique).
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004358:Drug Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072200:Ku Autoantigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes
keywords: BRCA1; MGMT; MSH2; neo-adjuvant chemotherapy; non-small cell lung cancer