title: An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial.
abstract: OBJECTIVE
  To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.
  
  
  METHODS
  The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.
  
  
  RESULTS
  RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25-2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26-3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79-6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97-3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23-0.97, P(interaction) = 0.042).
  
  
  CONCLUSIONS
  Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC.
authors.affiliation: UM de Biochimie des Cancers et Biothérapies, Département d'Anatomie et Cytologie Pathologiques, Institut Albert Bonniot, Université Joseph Fourier, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: de Fraipont
authors.forename: Guénaëlle
authors.initials: G
authors.lastname: Levallet
authors.forename: Christian
authors.initials: C
authors.lastname: Creveuil
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bergot
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.forename: Mounia
authors.initials: M
authors.lastname: Mounawar
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richard
authors.forename: Martine
authors.initials: M
authors.lastname: Antoine
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouquette
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Favrot
authors.forename: Didier
authors.initials: D
authors.lastname: Debieuvre
authors.forename: Denis
authors.initials: D
authors.lastname: Braun
authors.forename: Virginie
authors.initials: V
authors.lastname: Westeel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Quoix
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.forename: Franck
authors.initials: F
authors.lastname: Morin
authors.forename: Bernard
authors.initials: B
authors.lastname: Milleron
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C411762:RASSF1 protein, human; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D016190:Carboplatin; D066246:ErbB Receptors; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine