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• W2562711298 abstract "Abstract Introduction: The EML4-ALK (echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase) translocation represents a predictive driver mutation in non-small cell lung cancer (NSCLC). As EML4-ALK is both associated with resistance to EGFR inhibitors and druggability with FDA approved ALK kinase inhibitors, molecular profiling of the respective fusion transcripts is an important prerequisite for therapy. Ongoing clinical trials and development of new ALK inhibitors for personalized treatment also emphasize the need for development of accompanying diagnostics. Today's determination of EML4-ALK fusions is based on biopsies and fine-needle aspirates. These techniques are constrained by surgical complications, availability of tissue and sample heterogeneity. To overcome these challenges, the mutational analysis of fusion transcripts in plasma is expected to be a valuable benefit for non-surgical and longitudinal monitoring of EML4-ALK positive NSCLC patients. Experimental procedures: Using our proprietary column-based method to isolate vesicle-derived RNA from a few ml of patient plasma from NSCLC patients, we were able to consistently and reproducibly isolate sufficient amounts of high quality exoRNA. The purified exoRNA was subjected to RT-qPCR screening for EML4-ALK fusion transcripts, with assays designed to independently detect fusion transcripts of EML4-ALK variants v1, v2 and v3. During development of the qPCR, assay performance was characterized on synthetic nucleic acid oligos spiked into plasma of healthy human donors. The diagnostic assay was finally validated on time-matched tissue and plasma samples derived from NSCLC patients. Summary: Our data demonstrates the ability to detect rare predictive mutations in exosomal and other vesicular-derived RNA transcripts isolated from patient plasma. Here, NSCLC samples were characterized by monitoring their expression profile of EML4-ALK variants. The qPCR assays specifically detected the three major fusion transcript variants representing more than 70% of all EML4-ALK positive cases. The assay displayed high selectivity over wild type background and data showed correlation with tissue analysis. Iterative modeling of the assay significantly improved specificity and sensitivity towards its application as a diagnostic test. Conclusions: Liquid biopsies represent a low-risk and comprehensive method to screen for predictive cancer markers in plasma of NSCLC patients during longitudinal monitoring. The efficient isolation of exosomal/vesicle-derived RNA via spin column enables subsequent analysis of rare fusion transcripts for diagnostic development. As a proof of concept, we implemented a qPCR-based assay to determine EML4-ALK translocations in plasma from NSCLC patients, indicating the feasibility of developing a diagnostic test, which could facilitate effective personalized treatment. Citation Format: Kay Brinkmann, Daniel Enderle, Tina Koestler, Stefan Bentink, Jennifer Emenegger, Alexandra Spiel, Romy Mueller, Vincent O'Neill, Johan Skog, Mikkel Noerholm. Plasma-based diagnostics for detection of EML4-ALK fusion transcripts in NSCLC patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 545. doi:10.1158/1538-7445.AM2015-545" @default.
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• W2562711298 date "2015-08-01" @default.
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• W2562711298 title "Abstract 545: Plasma-based diagnostics for detection of EML4-ALK fusion transcripts in NSCLC patients" @default.
• W2562711298 doi "https://doi.org/10.1158/1538-7445.am2015-545" @default.
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