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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
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam ; ThromboDx B.V., Amsterdam.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, 1066-1075 p.Article in journal (Refereed) PublishedText
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 7, no 1, 1066-1075 p.
Keyword [en]
diagnostics, NSCLC, liquid biopsies, platelets, EML4-ALK
National Category
Cancer and Oncology
URN: urn:nbn:se:umu:diva-117842DOI: 10.18632/oncotarget.6279ISI: 000369950300077PubMedID: 26544515OAI: diva2:915462
Available from: 2016-03-30 Created: 2016-03-04 Last updated: 2016-03-30Bibliographically approved

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