An apoptotis methylation prognostic signature for early lung cancer in the IFCT-0002 trial
Menée sur des échantillons tumoraux prélevés sur 208 patients inclus dans un essai clinique d'évaluation d'une chimiothérapie néoadjuvante en traitement d'un cancer du poumon non à petites cellules de stade précoce, cette étude évalue l'association entre la méthylation du gène RASSF1A et la survie des patients
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 Stage I-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, RASSF1A and DAPK1 promoter methylation, and EGFR, 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 re-sampling 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 >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 to gemcitabine-cisplatin (adjusted HR=0.47; 95% CI [0.23-0.97], p for 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 to define 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 Stage I-II NSCLC.
Clinical Cancer Research , résumé, 2012