Originally published as JCO Early Release 10.1200/JCO.2009.22.6993 on August 10 2009

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Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK

From the Massachusetts General Hospital Cancer Center; Departments of Pathology and of Radiology, Massachusetts General Hospital; Hematology/Oncology Division, Beth Israel Deaconess Medical Center; and Department of Pathology, Brigham and Women's Hospital, Boston, MA; and Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Corresponding author: A. John Iafrate, MD, PhD, Department of Pathology, Massachusetts General Hospital, Warren 501c, 55 Fruit St, Boston, MA 02114; e-mail: aiafrate{at}partners.org.

Purpose The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non–small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK.

Patients and Methods Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing.

Results Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK–positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival.

Conclusion EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.

Supported in part by the National Institutes of Health Grant No. CA090578, by American Association for Cancer Research Grant No. 07-40-12-COST (D.B.C), and by internal funds from the Massachusetts General Hospital Cancer Center and MGH Pathology Department.

Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL.

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

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