Abstract
To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy. 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. 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). 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.
Highlights
Despite recent therapeutic advances, lung cancer is the primary cause of cancer-related deaths worldwide with a Authors' Affiliations: 1UM de Biochimie des cancers et Biotherapies; 2INSERM U823, Institut Albert Bonniot, Universite Joseph Fourier, Departement d'Anatomie et Cytologie Pathologiques; 3Po^le de Medecine Aigue Communautaire
A computed bootstrap resampling strategy led to a prognostic model, including Ras association domain family 1A (RASSF1A), death-associated protein kinase 1 (DAPK1), and tumor stage, dividing patients into three prognostic groups, with median overall survival (OS) ranging from 34 months for high-risk patients (HR for death 1⁄4 3.85, 95% CI: 1.79–6.40) to more than 84 months for moderate (HR 1⁄4 1.85, 95% CI: 0.97–3.52) and low-risk patients
RASSF1A methylation predicted longer disease-free survival (DFS) in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin
Summary
Lung cancer is the primary cause of cancer-related deaths worldwide with a Authors' Affiliations: 1UM de Biochimie des cancers et Biotherapies; 2INSERM U823, Institut Albert Bonniot, Universite Joseph Fourier, Departement d'Anatomie et Cytologie Pathologiques; 3Po^le de Medecine Aigue Communautaire. UF Oncologie thoracique, CHU de Grenoble, Grenoble; 4ER 3 INSERM «Cancers et Populations»; 5Service d'Anatomie Pathologique; 6Unite de Biostatistiques et de Recherche Clinique; 7Service de Pneumologie; 8Molecular Genetics Department, CHU de Caen, Caen; 9Laboratoire de Biochimie et Biologie moleculaire, Ho^pital de Hautepierre, CHU de Strasbourg; 10Service de Pneumologie, CHRU de Strasbourg, Strasbourg; 11International Agency of Research on Cancer (IARC), Molecular Carcinogenesis Group, Lyon; 12Service d'Anatomie Pathologique, Ho^pital Tenon, AP-HP; 13Intergroupe Francophone de Cancérologie Thoracique (IFCT) Unite de Recherche Clinique; 14Service de Pneumologie, Ho^pital Tenon, AP-HP, Paris; 15Service d'Anatomie Pathologique, Ho^pital Larrey, CHU de Toulouse, Toulouse; 16Service de Pneumologie, CH de Vesoul, Vesoul; 17Service de Pneumologie, CH de Briey, Briey; and 18Service de Pneumologie, CHU de Besancon, Besancon, France dismal prognosis. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The article was presented at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30–June 3, 2008, and at the World Conference on Lung Cancer, San Francisco, CA, July 31–August 4, 2009.
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