Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer

R Jonas A Nilsson, Niki Karachaliou, Jordi Berenguer, Ana Gimenez-Capitan, Pepijn Schellen, Cristina Teixido, Jihane Tannous, Justine L Kuiper, Esther Drees, Magda Grabowska, Marte van Keulen, Danielle A M Heideman, Erik Thunnissen, Anne-Marie C Dingemans, Santiago Viteri, Bakhos A Tannous, Ana Drozdowskyj, Rafael Rosell, Egbert F Smit, Thomas Wurdinger

Research output: Contribution to journalArticleAcademicpeer-review


PURPOSE: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers.

METHODS: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival.

RESULTS: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK- platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression.

CONCLUSIONS: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.

Original languageEnglish
Pages (from-to)1066-75
Number of pages10
Issue number1
Publication statusPublished - 5 Jan 2016


  • Adult
  • Aged
  • Aged, 80 and over
  • Blood Platelets/metabolism
  • Carcinoma, Non-Small-Cell Lung/blood
  • Crizotinib
  • Drug Monitoring/methods
  • Female
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Lung Neoplasms/blood
  • Male
  • Middle Aged
  • Oncogene Proteins, Fusion/blood
  • Outcome Assessment (Health Care)/methods
  • Prognosis
  • Proportional Hazards Models
  • Protein Kinase Inhibitors/therapeutic use
  • Pyrazoles/therapeutic use
  • Pyridines/therapeutic use
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction

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