title: Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.|ThromboDx B.V., Amsterdam, The Netherlands.
authors.forename: R Jonas A
authors.initials: RJ
authors.lastname: Nilsson
authors.affiliation: Translational Research Unit, Dr. Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain.
authors.forename: Niki
authors.initials: N
authors.lastname: Karachaliou
authors.affiliation: Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jordi
authors.initials: J
authors.lastname: Berenguer
authors.affiliation: Pangaea Biotech SL, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gimenez-Capitan
authors.affiliation: Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|ThromboDx B.V., Amsterdam, The Netherlands.
authors.forename: Pepijn
authors.initials: P
authors.lastname: Schellen
authors.affiliation: Pangaea Biotech SL, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teixido
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Jihane
authors.initials: J
authors.lastname: Tannous
authors.affiliation: Cancer Center Amsterdam, Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Justine L
authors.initials: JL
authors.lastname: Kuiper
authors.affiliation: Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Drees
authors.affiliation: Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Magda
authors.initials: M
authors.lastname: Grabowska
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Marte
authors.initials: M
authors.lastname: van Keulen
authors.affiliation: Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Danielle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.affiliation: Department of Pulmonary Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Anne-Marie C
authors.initials: AM
authors.lastname: Dingemans
authors.affiliation: Translational Research Unit, Dr. Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.affiliation: Pivotal, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Drozdowskyj
authors.affiliation: Translational Research Unit, Dr. Rosell Oncology Institute, Quirón Dexeus University Hospital, Barcelona, Spain.|Pangaea Biotech SL, Barcelona, Spain.|Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain.|Molecular Oncology Research (MORe) Foundation, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Cancer Center Amsterdam, Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.|ThromboDx B.V., Amsterdam, The Netherlands.|Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000097:blood / Q000235:genetics*; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib
keywords: EML4-ALK; NSCLC; diagnostics; liquid biopsies; platelets