Article

Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

Department of Pathology, Massachusetts General Hospital, Warren 501c, 55 Fruit St, Boston, MA 02114, USA.
Journal of Clinical Oncology (impact factor: 18.37). 09/2009; 27(26):4247-53. DOI:10.1200/JCO.2009.22.6993 pp.4247-53
Source: PubMed

ABSTRACT 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 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.
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.
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.

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Keywords

19 EML4-ALK tumors
 
adenocarcinoma histology
 
ALK expression
 
Asian ethnicity
 
clinical characteristics
 
distinct clinical characteristics
 
DNA sequencing
 
EML4-ALK fusion oncogene
 
EML4-ALK mutant tumors
 
EML4-ALK-positive tumors
 
following characteristics
 
genetic screening
 
molecular subset
 
non-small-cell lung cancers
 
signet ring cell subtype
 
similar response rates
 
situ hybridization
 
small subset
 
treatment outcomes
 
WT/WT cohorts