Abstract LB-053: Monitoring rearrangement of EML4-ALK in blood platelets predicts outcome to crizotinib treatment in non-small-cell lung cancer patients
Authors: Nilsson Jonas A. , Karachaliou Niki , Schellen Pepijn , Gimenez-Capitan Ana , Berenguer Jordi , Teixido Cristina , Kuiper Justine L. , Drees Esther , Grabowska Magda , van Keulen Marte , Tannous Jihane M. , Heideman Danielle A.M. , Thunnissen Erik , Dingemans Anne-Marie C. , Viteri Santiago , Tannous Bakhos A. , Drozdowskyj Ana , Rosell Rafael , Smit Egbert F. , Wurdinger Thomas 
Published: August 2015

Abstract
Background: Novel targeted therapies have been successfully used against subgroups of non-small-cell lung cancer (NSCLC) patients, however, despite initial good response the cancer will eventually relapse. One of those subgroups harbors a rearranged EML4-ALK fusion gene that makes them responsive to crizotinib treatment, but therapy resistance often soon occurs. Real-time monitoring of rearrangement status over the course of treatment will help identify patients showing therapy resistance, but monitoring through serial tumor biopsies has been an obstacle. Therefore, new blood-based ´liquid biopsy´ platforms need to be developed to monitoring biomarkers in the circulation. Here we present one platform using the ability of platelets to sequester RNA released by tumor cells and represent an attractive source for non-invasive biomarker assessment.
Methods: EML4-ALK rearrangements were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in platelets and plasma isolated from blood obtained from 77 NSCLC patients, 38 of whom had EML4-ALK-rearranged tumors. In a subset patients (n = 29) that were treated with crizotinib, progression-free survival (PFS) and overall survival (OS) were correlated with presence of EML4-ALK rearrangements in platelets.
Results: The study was designed with three parallel objectives: firstly to determine the sensitivity and specificity of detecting EML4-ALK rearrangements in platelets; secondly, to examine the potential impact of EML4-ALK rearrangement in platelets on outcome to crizotinib; thirdly, to test the feasibility of monitoring patients throughout treatment with EML4-ALK rearrangement assessment in platelets. Detection of EML4-ALK rearrangements in platelets demonstrated 65% sensitivity and 100% specificity. The PFS in patients treated with crizotinib was 3.7 months in patients with a positive EML4-ALK platelet status compared to 16 months for a negative EML4-ALK status (hazard ratio, 3.5; P = 0.02). Furthermore, longitudinal monitoring of EML4-ALK rearrangements in platelets was feasible, as demonstrated in an index patient where crizotinib resistance was observed two months prior to radiographic disease progression.
Conclusions: Platelets may provide a useful source for non-invasive assessment of EML4-ALK rearrangements and may prove useful for predicting outcome to crizotinib. Serial analyses of EML4-ALK rearrangements in platelets may help improve clinical decisions based on radiographic imaging alone by detecting resistance to therapy sooner.
Citation Format: Jonas A. Nilsson, Niki Karachaliou, Pepijn Schellen, Ana Gimenez-Capitan, Jordi Berenguer, Cristina Teixido, Justine L. Kuiper, Esther Drees, Magda Grabowska, Marte van Keulen, Jihane M. Tannous, Danielle A.M. Heideman, Erik Thunnissen, Anne-Marie C. Dingemans, Santiago Viteri, Bakhos A. Tannous, Ana Drozdowskyj, Rafael Rosell, Egbert F. Smit, Thomas Wurdinger. Monitoring rearrangement of EML4-ALK in blood platelets predicts outcome to crizotinib treatment in non-small-cell lung cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-053. doi:10.1158/1538-7445.AM2015-LB-053