An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial.

Florence de Fraipont (1) , Guénaëlle Levallet , Christian Creveuil , Emmanuel Bergot (2) , Michèle Beau-Faller (3) , Mounia Mounawar (4) , Nicolas Richard (5) , Martine Antoine (6, 7, 8) , Isabelle Rouquette , Marie-Christine Favrot (9) , Didier Debieuvre (10) , Denis Braun , Virginie Westeel (11) , Elisabeth Quoix (12) , Elisabeth Brambilla (1) , Pierre Hainaut (13) , Denis Moro-Sibilot (1, 7, 14) , Franck Morin (15) , Bernard Milleron (8) , Gérard Zalcman (2) , Non Renseigné

1 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble
2 Service de pneumologie [CHU Caen]
3 Laboratoire de Biochimie et de Biologie Moléculaire
4 Unit of Environment Cancer Epidemiology
5 Service de Génétique [CHU Caen]
6 Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux
7 IFCT - Intergroupe Francophone de Cancérologie Thoracique [Paris]
8 CHU Tenon [AP-HP]
9 CIB - Centre d'innovation en biologie
10 Service de Pneumologie
11 CEF2P / CARCINO - Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181)
12 Service de pneumologie
13 IACR - International Agency for Cancer Research
14 Pôle Médecine Aigüe Communautaire Pneumologie
15 Amplitude Systèmes

PURPOSE: To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: 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.

Domaines: Cancer

Florence de Fraipont, Guénaëlle Levallet, Christian Creveuil, Emmanuel Bergot, Michèle Beau-Faller, et al.. An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial.. Clinical Cancer Research, 2012, 18 (10), pp.2976-2786. ⟨10.1158/1078-0432.CCR-11-2797⟩. ⟨hal-00718845⟩