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.
Highlights
The advances in our understanding of cancer biology over the last two decades have underscored the genomic heterogeneity among tumors of the same type, as well as similar driver mechanisms in different cancer types, enabling both tailored approaches to individual patient care as well as pan-tumor therapeutic indications [1–4]
Broader whole exome sequencing (WES; note all abbreviations/acronyms are available in the S1 Appendix, Table S1 in S1 Appendix [all supplemental tables are located in S1 Appendix]) or whole genome sequencing (WGS) raise different challenges for clinicians
The results reported with F1CDx were similar to the clinical efficacy outcomes as reported in the device validation (DV) population and recently compared to the efficacy analysis of over 1,700 patients representing over 20 tumor types with tumor mutational burden (TMB) determined by WES who were treated with pembrolizumab in a series of 12 clinical trials
Summary
The advances in our understanding of cancer biology over the last two decades have underscored the genomic heterogeneity among tumors of the same type, as well as similar driver mechanisms in different cancer types, enabling both tailored approaches to individual patient care as well as pan-tumor therapeutic indications [1–4]. The rapidly expanding repertoire of targeted cancer therapies provides significant challenges for oncologists treating patients, as keeping up with companion diagnostic approvals, clinical trials, and evolving understanding of cancer biology can exceed the capacity of many physicians. Validated testing solutions that comprehensively cover actionable alterations and deliver the latest literature-based guidance on potential treatment options, along with relevant clinical trials and levels of evidence, offer a streamlined and comprehensive solution to oncologists and provide patients with reassurance that even rare but potentially treatable alterations can be identified [7–13]. WES evaluates all exonic protein-coding regions of the human genome, encompassing ~30 million base pairs (~1% of the human genome), while WGS aims to sequence the entire genome These efforts produce data from an excessive breadth of the genome, but generally deliver lower depth of sequencing that results in a higher LoD relative to broad-panel assays [21, 22]. WES and WGS approaches can entail higher cost, complex analytics, and longer turnaround time, but critically, they may burden the report recipient with many variants of unknown significance (VUS) from genes not relevant to therapeutic decision-making for the patient [23–27]
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