ALK gene rearrangements in unselected caucasians with non-small cell lung carcinoma (NSCLC).

Abstract

10533 Background: Transforming rearrangements of the ALK gene have been reported in a subset of NSCLC, commonly fusing the ALK kinase domain with EML4 promoter but rarer fusion partners (TFG and KIF5B) have also been described. ALK is a valid clinical target based on phase I clinical data with dual ALK/MET inhibitor. We investigated the cytogenetic patterns of ALK rearrangements using FISH and the molecular and clinical characteristics associated with ALK+ in an unselected NSCLC population. Methods: Cohort included 447 NSCLC with previous EGFR and MET copy number gain (CNG) available; median age at diagnosis = 66 years, 83% male, 52% former and 35% current smokers; 52% of tumors were adenocarcinoma/BAC, stage I to IV was 37%, 22%, 27%, and 14%, respectively. Dual color FISH analyses were performed with ALK break-apart probe (Abbott Molecular) and 3 novel fusion probe sets specific for EML4-ALK, KIF5B-ALK and TFG-ALK. Results: Using the break apart probe, 12 patients (2.68%) were identified as ALK+. Multiple different cytogenetic patterns were observed, but virtually all carried the EML4-ALK fusion when specific probe sets were used. Using logistic regression analyses, higher odds were verified for ALK+ among males vs. females (p = 0.03), never vs. ever smokers (p = 0.005), adenocarcinoma vs. other histologies (p = 0.0013), and younger vs. older age (p = 0.08). No association was found between ALK+ and clinical stage, EGFR or MET CNG. There was no association between survival and ALK+ after adjusting for patient's gender, smoking history, histology and age (HR = 0.70; 95% CI 0.0256, 1.913, p = 0.48). Conclusions: In this large study of unselected Caucasian NSCLC patients, ALK+ was associated with male gender, never smoking status and adenocarcinoma histology suggesting these factors could be used to enrich ALK screened populations. The specific FISH probe sets identified EML4- ALK in different FISH patterns observed with the ALK rearrangement probe. ALK+ is distinct from EGFR and MET CNG, suggesting independent molecular mechanisms. ALK+ showed no significant prognostic impact, the observed favorable effect was unstable most likely due to the low number of ALK+. No significant financial relationships to disclose.