Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors

Abstract

FoundationOne®CDx (F1CDx) is a United States (US) Food and Drug Administration (FDA)-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. F1CDx utilizes next-generation sequencing (NGS)-based comprehensive genomic profiling (CGP) technology to examine 324 cancer genes in solid tumors. F1CDx reports known and likely pathogenic short variants (SVs), copy number alterations (CNAs), and select rearrangements, as well as complex biomarkers including tumor mutational burden (TMB) and microsatellite instability (MSI), in addition to genomic loss of heterozygosity (gLOH) in ovarian cancer. CGP services can reduce the complexity of biomarker testing, enabling precision medicine to improve treatment decision-making and outcomes for cancer patients, but only if test results are reliable, accurate, and validated clinically and analytically to the highest standard available. The analyses presented herein demonstrate the extensive analytical and clinical validation supporting the F1CDx initial and subsequent FDA approvals to ensure high sensitivity, specificity, and reliability of the data reported. The analytical validation included several in-depth evaluations of F1CDx assay performance including limit of detection (LoD), limit of blank (LoB), precision, and orthogonal concordance for SVs (including base substitutions [SUBs] and insertions/deletions [INDELs]), CNAs (including amplifications and homozygous deletions), genomic rearrangements, and select complex biomarkers. The assay validation of >30,000 test results comprises a considerable and increasing body of evidence that supports the clinical utility of F1CDx to match patients with solid tumors to targeted therapies or immunotherapies based on their tumor’s genomic alterations and biomarkers. F1CDx meets the clinical needs of providers and patients to receive guideline-based biomarker testing, helping them keep pace with a rapidly evolving field of medicine.

Tumor Mutational Burden as a Predictor of First-Line Immune Checkpoint Inhibitor Versus Carboplatin Benefit in Cisplatin-Unfit Patients With Urothelial Carcinoma

“…A number of panels with faster TAT can estimate TMB, such as the FoundationO-neCDx assay, with a reported median TAT of 10.9 days in 2021. 36 However, recent TMB harmonization effort by Friends of Cancer Research using a common set of cell lines and patient samples determined that TMB calculation can vary considerably from platform to platform, dependent on panel size, gene content, and bioinformatic filtering. 10 The considerable between-platform variability of TMB measurements underscores the importance of demonstrated associations with clinical outcomes per platform.…”

Comprehensive Genomic Profiling (CGP)-Informed Personalized Molecular Residual Disease (MRD) Detection: An Exploratory Analysis from the PREDATOR Study of Metastatic Colorectal Cancer (mCRC) Patients Undergoing Surgical Resection

“…In this study, genomic DNA from resected tumor tissue was collected and extracted as described previously [ 14 ]. The CGP of tumor DNA was performed retrospectively using a method adapted from the study by Milbury et al to identify patient-specific alterations [ 29 ]. Briefly, the DNA was extracted from FFPE archival patient samples and was end-repaired, A-tailed, and adapters were ligated, followed by hybrid capture-based next-generation sequencing (NGS) on the Illumina ® HiSeq 4000 (Illumina, Inc., San Diego, CA, USA).…”

Comprehensive Genomic Profiling in the Management of Ovarian Cancer—National Results from Croatia

“…Comprehensive genomic profiling is approved by FDA and has undergone many validations [ 23 , 24 ]. However, to confirm its results, we explored and compared its compatibility with locally performed BRCA testing and immunohistochemistry testing for TP53 mutations in patients at a single institution.…”