Clinical Research Papers:
Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer
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R. Jonas A. Nilsson1,2,3,*, Niki Karachaliou4,*, Jordi Berenguer1, Ana Gimenez-Capitan5, Pepijn Schellen1,3, Cristina Teixido5, Jihane Tannous6, Justine L. Kuiper7, Esther Drees1, Magda Grabowska1, Marte van Keulen6, Danielle A. M. Heideman8, Erik Thunnissen8, Anne-Marie C. Dingemans9, Santiago Viteri4, Bakhos A. Tannous6, Ana Drozdowskyj10, Rafael Rosell4,5,11,12,**, Egbert F. Smit7,** and Thomas Wurdinger1,3,6,**
1 Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands
2 Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
3 ThromboDx B.V., Amsterdam, The Netherlands
4 Translational Research Unit, Dr, Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain
5 Pangaea Biotech SL, Barcelona, Spain
6 Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA
7 Cancer Center Amsterdam, Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands
8 Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
9 Department of Pulmonary Diseases, Maastricht University Medical Center, Maastricht, The Netherlands
10 Pivotal, Madrid, Spain
11 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
12 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain
* These two authors are co-first authors of the manuscript
** These three authors are co-senior authors of the manuscript
Thomas Wurdinger, email:
Keywords: diagnostics, NSCLC, liquid biopsies, platelets, EML4-ALK
Received: August 23, 2015 Accepted: October 06, 2015 Published: November 02, 2015
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.
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