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. 2020 Sep 25;15(9):e0237802.
doi: 10.1371/journal.pone.0237802. eCollection 2020.

Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin

Ryan Woodhouse  1 , Meijuan Li  2 , Jason Hughes  3 , David Delfosse  4 , Joel Skoletsky  4 , Pei Ma  2 , Wei Meng  2 , Ninad Dewal  2 , Coren Milbury  4 , Travis Clark  5 , Amy Donahue  6 , Dan Stover  7 , Mark Kennedy  3 , Jennifer Dacpano-Komansky  8 , Christine Burns  4 , Christine Vietz  9 , Brian Alexander  10 , Priti Hegde  6 , Lucas Dennis  11
Affiliations

Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin

Ryan Woodhouse et al. PLoS One. .

Abstract

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne®Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.

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Conflict of interest statement

The authors have the following interests. At the time of this research RW, ML, JH, DD, JS, PM, WM, ND, CM, TC, AD, DS, MK, CB, CV, BA, PH, and LD were employed by Foundation Medicine, Inc., the funder of this study. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1
Fig 1. FoundationOne Liquid CDx assay utilization overview.
FoundationOne Liquid CDx was designed to allow comprehensive genomic profiling, understanding that shed of tumor DNA can be variable depending on a patient’s clinical characteristics.
Fig 2
Fig 2. Box blots representing limits of detection (LoD) for variant categories in which 1069 tests were performed and 2180 variants were analyzed.
A. Short variant and rearrangement LoD, B. Copy number LoD, C. bTMB component LoD. MAF–Mutant Allele Fraction.
See this image and copyright information in PMC

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