MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial

// Guenaelle Levallet 1 , Fatemeh Dubois 2 , Pierre Fouret 3 , Martine Antoine 4 , Solenn Brosseau 2,5,6 , Emmanuel Bergot 2,5 , Michele Beau-Faller 7 , Valerie Gounant 6,8 , Elisabeth Brambilla 9 , Didier Debieuvre 10 , Olivier Molinier 11 , Francoise Galateau-Salle 1 , Julien Mazieres 12 , Elisabeth Quoix 13 , Jean-Louis Pujol 14 , Denis Moro-Sibilot 15 , Alexandra Langlais 16 , Franck Morin 16 , Virginie Westeel 17 and Gerard Zalcman 5,6,18,19 1 Service d’Anatomie et Cytologie Pathologique, Centre Hospitalier Universitaire de Caen, Normandie Universite, Caen, France 2 Normandie Universite; UMR 1086 INSERM, Caen, France 3 Service d’Anatomie Pathologique, Pitie-Salpetriere, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 4 Service d’Anatomie Pathologique, Hopital Tenon, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 5 Service de Pneumologie et Oncologie Thoracique, Centre Hospitalier Universitaire de Caen, Normandie Universite, Caen, cedex, France 6 Service d’Oncologie Thoracique, Hopital Bichat-Claude Bernard, AP-HP, Universite Paris-Diderot, Paris, France 7 Laboratoire de Biochimie et Biologie moleculaire, Hopital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Universite de Strasbourg, BP426 Strasbourg, Cedex, France 8 Service de Pneumologie, Hopital Tenon, AP-HP, Universite Pierre et Marie Curie (UPMC), Paris, France 9 Service d’Anatomie Pathologique, Hopital Albert Michallon, Centre Hospitalier Universitaire de Grenoble, La Tronche, France 10 Service de Pneumologie, GHRMSA-Centre Hospitalier Eric Muller, Mulhouse, France 11 Service de Pneumologie, Centre Hospitalier du Mans, Le Mans, France 12 Service de Pneumologie, Hopital Larrey, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse III, Toulouse, France 13 Service de Pneumologie, Nouvel Hopital Civil, Hospices Civils de Strasbourg, Universite de Strasbourg, BP426 Strasbourg, Cedex, France 14 Service de Pneumologie, Centre Hospitalier Universitaire Arnaud de Villeneuve, Universite de Montpellier, Montpellier, France 15 Unite d’Oncologie Thoracique–Pneumologie, CHU de Grenoble, INSERM U823, Grenoble, France 16 Intergroupe Francophone de Cancerologie Thoracique (IFCT), Paris, France 17 Service de Pneumologie, Hopital Jean-Minjoz, Centre Hospitalier Universitaire de Besancon, Universite de Franche-Comte, Besancon, France 18 CIC INSERM 1425-CLIP2 Paris-Nord, Hopital Bichat-Claude Bernard, AP-HP, Paris, France 19 On Behalf of the IFCT (Intergroupe Francophone de Cancerologie Thoracique) Correspondence to: Gerard 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). O 6 MGMT 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.