title: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, Massachusetts General Hospital, Warren 501c, 55 Fruit St, Boston, MA 02114, USA.
authors: Alice T
authors: AT
authors: Shaw
authors: Beow Y
authors: BY
authors: Yeap
authors: Mari
authors: M
authors: Mino-Kenudson
authors: Subba R
authors: SR
authors: Digumarthy
authors: Daniel B
authors: DB
authors: Costa
authors: Rebecca S
authors: RS
authors: Heist
authors: Benjamin
authors: B
authors: Solomon
authors: Hannah
authors: H
authors: Stubbs
authors: Sonal
authors: S
authors: Admane
authors: Ultan
authors: U
authors: McDermott
authors: Jeffrey
authors: J
authors: Settleman
authors: Susumu
authors: S
authors: Kobayashi
authors: Eugene J
authors: EJ
authors: Mark
authors: Scott J
authors: SJ
authors: Rodig
authors: Lucian R
authors: LR
authors: Chirieac
authors: Eunice L
authors: EL
authors: Kwak
authors: Thomas J
authors: TJ
authors: Lynch
authors: A John
authors: AJ
authors: Iafrate
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D011905:Genes, ras / Q000235:genetics; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib