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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

121 Citations (Web of Science)

Abstract

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)1066-1075
JournalOncotarget
Volume7
Issue number1
DOIs
Publication statusPublished - 5 Jan 2016

Keywords

  • diagnostics
  • NSCLC
  • liquid biopsies
  • platelets
  • EML4-ALK

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