Originally published as JCO Early Release 10.1200/JCO.2008.19.1635 on March 2 2009

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Increased MET Gene Copy Number Negatively Affects Survival of Surgically Resected Non–Small-Cell Lung Cancer Patients

From the Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Department of Oncology-Hematology; University of Milan School of Medicine, Department of Pathology, IRCCS Istituto Clinico Humanitas, Rozzano; Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chiety; CINECA, Interuniversity Consortium, Bologna, Italy; University of Colorado Cancer Center, Department of Medicine/Medical Oncology, Aurora, CO; and the University Hospital, Division of Molecular Pathology, Basel, Switzerland.

Corresponding author: Federico Cappuzzo, MD, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, via Manzoni 56, 20089 Rozzano, Italy; e-mail: federico.cappuzzo{at}humanitas.it.

Purpose To investigate the prognostic role of genomic gain for MET and epidermal growth factor receptor (EGFR) genes in surgically resected non–small-cell lung cancer (NSCLC).

Patients and Methods This retrospective study included 447 NSCLC patients with available tumor tissue from primary lung tumor and survival data. EGFR and MET status was evaluated by fluorescent in situ hybridization (FISH) in tissue microarray sections.

Results EGFR FISH results were obtained in 376 cases. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 10.4% and 32.4% of cases, respectively. EGFR FISH-positive patients had a nonsignificant shorter survival than EGFR FISH-negative patients (P = .4). Activating EGFR mutations were detected in 9.7% of 144 stage I-II disease with no impact on survival. MET FISH analysis was performed in 435 cases. High MET gene copy number (mean 5 copies/cell) was observed in 48 cases (MET+, 11.1%), including 18 cases with true gene amplification (4.1%). MET+ status was associated with advanced stage (P = .01), with grade 3 (P = .016) and with EGFR FISH+ result (P < .0001). No patient with activating EGFR mutation resulted MET+. In the whole population, MET-positive patients had shorter survival than MET-negative patients (P = .005). Multivariable model confirmed that MET-negative patients had a significant reduction in the risk of death than MET-positive patients (hazard ratio, 0.66; P = .04).

Conclusion MET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.

Supported in part by Italian Association for Cancer Research (F.C.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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