In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P ‫؍‬ 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR T790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR T790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.lung adenocarcinoma ͉ XL880

who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan-Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33-89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n ¼ 1) and minimally invasive adenocarcinoma (n ¼ 8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant (n ¼ 29), papillary predominant (n ¼ 143) and acinar predominant (n ¼ 232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n ¼ 13), colloid predominant (n ¼ 9), solid predominant (n ¼ 67) and micropapillary predominant (n ¼ 12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (Po0.001). Among the clinicopathological factors, stage 1B versus 1A (Po0.001), male sex (Po0.008), high histological grade (Po0.001), vascular invasion (P ¼ 0.002) and necrosis (Po0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P ¼ 0.04) and invasive tumor size adjusted by the percentage of lepidic growth (Po0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P ¼ 0.038), male gender (P ¼ 0.007), tumor invasive size (P ¼ 0.026) and necrosis (P ¼ 0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in

Although prognostic gene expression signatures for survival in early stage lung cancer have been proposed, for clinical application it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether