Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours

Abstract

Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we show across a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The more prevalent actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.

Next-Generation Sequencing-Based Evaluation of the Actionable Mutational Landscape in Solid Tumors: the “MOZART” Prospective Observational Study

“…These technical limitations translate into the loss of potential therapeutic opportunities for many patients. At our center, we have addressed this challenge by performing precision oncology genomic testing utilizing a comprehensive precision oncology next generation sequencing (NGS) assay 7,8 , to identify the prevalence of potentially actionable mutations in a large cohort of patients with heavily-pretreated metastatic solid tumors, where therapeutic options are usually limited. Here we report the analysis of test trending data from this large screening programme to investigate the prevalence of actionable mutations directed at either the prescription of speci c salvage targeted treatments (off-label or in indication) or alternatively to recruit patients to the most appropriate clinical trials.…”