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Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer
- Source :
- Oncotarget, Nilsson, R J A, Karachaliou, N, Berenguer, J, Gimenez-Capitan, A, Schellen, P, Teixido, C, Tannous, J, Kuiper, J L, Drees, E, Grabowska, M, van Keulen, M, Heideman, D A M, Thunnissen, E, Dingemans, A-M C, Viteri, S, Tannous, B A, Drozdowskyj, A, Rosell, R, Smit, E F & Wurdinger, T 2016, ' Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer ', Oncotarget, vol. 7, no. 1, pp. 1066-1075 ., Oncotarget, 7(1), 1066-75. Impact Journals, Nilsson, R J A, Karachaliou, N, Berenguer, J, Gimenez-Capitan, A, Schellen, P, Teixido, C, Tannous, J, Kuiper, J L, Drees, E, Grabowska, M, van Keulen, M, Heideman, D A M, Thunnissen, E, Dingemans, A-M C, Viteri, S, Tannous, B A, Drozdowskyj, A, Rosell, R, Smit, E F & Wurdinger, T 2016, ' Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer ', Oncotarget, vol. 7, no. 1, pp. 1066-75 . https://doi.org/10.18632/oncotarget.6279, Oncotarget, 7(1), 1066-1075. Impact Journals, Oncotarget, 7(1), 1066-1075. Impact Journals LLC
- Publication Year :
- 2015
-
Abstract
- // R. Jonas A. Nilsson 1,2,3,* , Niki Karachaliou 4,* , Jordi Berenguer 1 , Ana Gimenez-Capitan 5 , Pepijn Schellen 1,3 , Cristina Teixido 5 , Jihane Tannous 6 , Justine L. Kuiper 7 , Esther Drees 1 , Magda Grabowska 1 , Marte van Keulen 6 , Danielle A. M. Heideman 8 , Erik Thunnissen 8 , Anne-Marie C. Dingemans 9 , Santiago Viteri 4 , Bakhos A. Tannous 6 , Ana Drozdowskyj 10 , Rafael Rosell 4,5,11,12,** , Egbert F. Smit 7,** and Thomas Wurdinger 1,3,6,** 1 Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden 3 ThromboDx B.V., Amsterdam, The Netherlands 4 Translational Research Unit, Dr, Rosell Oncology Institute, Quiron 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 Correspondence to: Thomas Wurdinger, email: // Keywords : diagnostics, NSCLC, liquid biopsies, platelets, EML4-ALK Received : August 23, 2015 Accepted : October 06, 2015 Published : November 02, 2015 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.
- Subjects :
- 0301 basic medicine
Oncology
Male
Pathology
Lung Neoplasms
Oncogene Proteins, Fusion
Pyridines
Kaplan-Meier Estimate
NSCLC
liquid biopsies
0302 clinical medicine
hemic and lymphatic diseases
Carcinoma, Non-Small-Cell Lung
Outcome Assessment, Health Care
diagnostics
Platelet
In Situ Hybridization, Fluorescence
Aged, 80 and over
Reverse Transcriptase Polymerase Chain Reaction
Hazard ratio
Middle Aged
University hospital
Prognosis
3. Good health
030220 oncology & carcinogenesis
platelets
Female
Non small cell
Drug Monitoring
medicine.drug
Adult
Blood Platelets
medicine.medical_specialty
EML4-ALK
Translational research
03 medical and health sciences
Crizotinib
Internal medicine
medicine
Humans
Lung cancer
Protein Kinase Inhibitors
Aged
Proportional Hazards Models
Cancer och onkologi
business.industry
Cancer
Reproducibility of Results
medicine.disease
030104 developmental biology
Cancer and Oncology
Pyrazoles
Clinical Research Paper
business
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....46e65ec520d82d00f12fe5efc3a222a7