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Keywords: tumor mutation burden, TMB, microsatellite instability, MSI, companion diagnostic, CDx, analytical validation
To support the analytical performance of FoundationOne®Liquid CDx (F1LCDx) assay in measuring blood tumor mutation burden (bTMB), sufficient samples covering a wide range of bTMB scores are needed to adequately demonstrate the precision of qualitative bTMB reporting. However, blood sample selection is restricted by sample availability due to limited DNA yield, and it is extremely burdensome to identify a sample with a particular combination of variant allele frequencies (VAFs). A simulation approach through simulating various bTMB sample profiles across variant VAFs and bTMB scores was proposed. bTMB sample profiles were constructed based on three key components: 1) number of component variants, 2) proportion of variants in each variant category, 3) VAF level of individual variant and closeness to the limit of detection (LoD). Different combinations of variant VAF levels were assessed with a fixed number of variants, and the number of variants was varied across a wide range of possible values.
A fraction-based (FB) caller for measuring microsatellite instability (MSI) with improved analytical sensitivity was developed for the FoundationOne®CDx (F1CDx) assay using DNA derived from a wide range of Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue types representing a pan-solid tumor intended use (IU) population. Analytical validation studies were conducted to assess the performance of the F1CDx assay in calling MSI status based on a pre-specified MSI score cutoff across multiple tumor types with a wide range of scores. These studies demonstrated the F1CDx assay MSI calling performance using the FB-MSI caller under different study designs in a pan-tumor setting.