Clinicopathologic features of EML4-ALK mutant lung cancer

Abstract

11021 Background: EML4-ALK is a novel fusion oncogene in non-small cell lung cancer (NSCLC). The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. The clinicopathologic features of these patients have not been definitively established. Furthermore, the clinical outcome of these patients is unknown. Here we present the largest series of EML4-ALK mutants to date, and the first analysis of treatment response and survival in metastatic patients with and without EML4-ALK. Methods: Patients with NSCLC were selected for genetic screening based on 2 or more of the following characteristics: female gender, Asian ethnicity, never or light smoking history, and adenocarcinoma histology. The EML4-ALK inversion was identified using FISH and confirmed by IHC for ALK expression. EGFR mutation status was determined by direct sequencing of EGFR exons 18–21. Results: Of 141 patients screened, 18 (13%) were ALK mutant, 31 (22%) were EGFR mutant, and 92 (65%) were wild-type (WT) for both ALK and EGFR. The majority of tumors were adenocarcinomas, with ALK but not EGFR mutant tumors strongly associated with the signet ring cell subtype. Compared to the EGFR mutant and WT cohorts, patients with ALK mutant tumors were significantly younger (median age 52.5 vs 64 yrs, p=0.003), and more likely to be male (61% vs 30%, p=0.015). ALK mutants, like EGFR mutants, were also more likely to be light/never smokers compared with WT patients (100% vs 43%, p<0.001). Among patients with metastatic disease, there was a significant association between EML4-ALK and resistance to EGFR TKIs, with no responses by RECIST in the ALK cohort. ALK mutants and WT patients showed similar response rates to platinum-based chemotherapy (60% vs 65%, p=1), and had similar 1-yr survival rates (81% vs. 66%, p=0.43). Conclusions: EML4-ALK defines a new molecular subset of NSCLC with distinct clinical and pathologic characteristics. The frequency of EML4-ALK is particularly high in light/never smokers without EGFR mutation. These patients do not benefit from EGFR TKIs and should be treated with other standard agents or ALK targeted therapies. [Table: see text]