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 (1) , Fatéméh Dubois (2) , Pierre Fouret (3) , Martine Antoine (4) , Solenn Brosseau (2, 5, 6) , Emmanuel Bergot (2, 5) , Michèle Beau-Faller (7) , Valérie Gounant (4, 6) , Elisabeth Brambilla (8) , Didier Debieuvre (9) , Olivier Molinier (10) , Françoise Galateau-Sallé (1) , Julien Mazieres (11) , Elisabeth Quoix (12) , Jean-Louis Pujol (13, 14) , Denis Moro-Sibilot (15, 8) , Alexandra Langlais (16) , Franck Morin (16) , Virginie Westeel (17) , Gérard Zalcman (5, 6)

1 Laboratoire d'Anatomie Pathologique [CHU Caen]
2 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
3 CHU Pitié-Salpêtrière [AP-HP]
4 CHU Tenon [AP-HP]
5 Service de pneumologie [CHU Caen]
6 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
7 Hôpital de Hautepierre [Strasbourg]
8 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
9 CH E.Muller Mulhouse - Centre Hospitalier Emile Muller [Mulhouse]
10 Centre Hospitalier Le Mans (CH Le Mans)
11 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
12 Nouvel Hôpital Civil de Strasbourg
13 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
14 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
15 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
16 IFCT - Intergroupe Francophone de Cancérologie Thoracique [Paris]
17 Service de Pneumologie, oncologie thoracique et allergologie respiratoire [CHRU Besançon]

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.

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

Domaines: Cancer; Pneumologie et système respiratoire; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Guénaëlle Levallet, Fatéméh Dubois, Pierre Fouret, Martine Antoine, Solenn Brosseau, et al.. MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial. Oncotarget, 2017, 8 (3), pp.4313-4329. ⟨10.18632/oncotarget.14025⟩. ⟨hal-01550456⟩