RT Journal Article
SR Electronic
T1 An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 2976
OP 2986
DO 10.1158/1078-0432.CCR-11-2797
VO 18
IS 10
A1 de Fraipont, Florence
A1 Levallet, Guénaëlle
A1 Creveuil, Christian
A1 Bergot, Emmanuel
A1 Beau-Faller, Michèle
A1 Mounawar, Mounia
A1 Richard, Nicolas
A1 Antoine, Martine
A1 Rouquette, Isabelle
A1 Favrot, Marie-Christine
A1 Debieuvre, Didier
A1 Braun, Denis
A1 Westeel, Virginie
A1 Quoix, Elisabeth
A1 Brambilla, Elisabeth
A1 Hainaut, Pierre
A1 Moro-Sibilot, Denis
A1 Morin, Franck
A1 Milleron, Bernard
A1 Zalcman, Gérard
YR 2012
UL http://clincancerres.aacrjournals.org/content/18/10/2976.abstract
AB 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, Pinteraction = 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. Clin Cancer Res; 18(10); 2976–86. ©2012 AACR.