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.
Highlights
As availability of precision therapies expands [1], there is an increasing reliance on genomic profiling assays to help identify the most relevant treatment options for advanced cancer patients [2,3,4]
Due to intratumor heterogeneity, a tumor biopsy may represent a small sample of the overall tumor cell population, a limitation that can potentially be overcome with liquid biopsy [10, 16,17,18]
A PPA of 71.7% and an NPA of 100% for the detection of eligible PIK3CA alterations were observed as compared to the tumor tissue polymerase chain reaction (PCR) clinical trial assay (CTA)
Summary
As availability of precision therapies expands [1], there is an increasing reliance on genomic profiling assays to help identify the most relevant treatment options for advanced cancer patients [2,3,4]. With 38% of stage IV non-small cell lung cancer (NSCLC) patients in one single-center cohort study having insufficient quantity or quality of DNA for NGS. Often referred to as liquid biopsy assays, circulating cell-free DNA (cfDNA)-based assays, are a growing method for providing genomic profiling results to patients. CfDNAbased testing is established for patients who are unable to provide evaluable tissue or when tissue quality or quantity is insufficient in a number of cancers [10,11,12,13]. Tissuebased CGP has been shown to have improved clinical value compared to non-CGP testing, and liquid testing will likely add value based on its ability to find complementary information and provide biomarker results for patients unable to receive tissue testing [19]
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