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

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.