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 journalArticleAcademic

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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
Number of pages10
JournalOncotarget
Volume7
Issue number1
DOIs
Publication statusPublished - 2016
Externally publishedYes

Bibliographical note

Funding Information:
Financial support was provided by European Research Council E8626 (RJAN, EFS, TW) and 336540 (TW), the Dutch Organisation of Scientific Research 93612003 and 91711366 (TW), the NIH 2012D006044 (BAT), CFF Norrland (RJAN), and the Swedish Research Council (RJAN). Work in Dr Rosell's laboratory is partially supported by a grant from "La Caixa" Foundation and by Redes Temáticas de Investigación en Cáncer (RD12/0036/0072). Employees of thromboDx BV and Pangaea Biotech SL contributed in this study.

Publisher Copyright:
© 2015. Oncotarget.

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