A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC)

Abstract

7026 Background. Although stage-specific classification identifies appropriate populations for adjuvant chemotherapy, this is likely an imprecise predictor for the individual patient with early stage NSCLC. Methods. Using previously-described methodologies that employ DNA microarray data, multiple gene expression profiles (‘metagenes’) that predict risk of recurrence in patients with stage I disease were identified. This analysis used an initial ‘test’ cohort of patients with NSCLC (n = 89) that represented an equal mix of squamous cell and adenocarcinoma. Also, each histologic subset had equal number of patients who survived more than 5 years and those who died within 2.5 years of initial diagnosis. The performance of the metagene-based model generated on the training cohort was then evaluated in independent ‘validation’ sets, including two multi-center cooperative group studies (ACOSOG Z0030 and CALGB 9761). Importantly, the CALGB validation was performed in a blinded fashion. Results. Classification tree analyses that sample multiple gene expression profiles were used to develop a model of recurrence, termed the Lung Metagene Model, that accurately assesses prognosis (risk of recurrence and survival), performing significantly (p<0.001, odds ratio: 16.1, multivariate analysis) better than pathologic stage, T-size, nodal status, age, gender, histologic subtype and smoking history. The accuracy of prognosis using the Lung Metagene Model exceeded 90% (leave-one-out cross validation) in the initial training set (n = 89), 72% in the ACOSOG (n = 25), and 81% in the CALGB (n = 84) datasets. The prognostic accuracy was consistent across histologic subtypes and stages of NSCLC. Importantly, this provides an opportunity to re-classify stage IA patients to identify a subset of ‘high risk’ patients that may benefit from adjuvant chemotherapy. Further, stage IB and II patients identified as ‘low risk’ for recurrence, and who present co-morbidities, could potentially be candidates for observation, and those patients predicted to be at ‘high risk’ may benefit from novel therapeutic trials. Conclusions. The Lung Metagene Model provides a mechanism to refine the estimation of an individual patient’s risk for disease recurrence and thus guide the use of adjuvant chemotherapy in NSCLC. No significant financial relationships to disclose.