FDA-led consortium studies advance quality control of targeted next generation sequencing assays for precision oncology

Abstract

Cancer is the second leading cause of mortality worldwide despite tremendous advances in treatment. The promise of precision oncology depends on accurate characterization of tumor mutations and subsequent therapy selection. The lack of tumor reference samples along with the associated next generation sequencing (NGS) technical assessments has hindered the development of NGS assays and the realization of benefits for precision oncology. The summarized results and recommendations of several seminal SEQC2 studies along with a vision of the changing landscape of precision oncology and anticipated next steps by the SEQC2 consortium are reported. Importantly, these studies utilized a new robust reference sample material which was developed and constructed to support multiple DNA and RNA-based NGS assay studies. These studies focused on a wide variety of precision oncology assay scenarios and provided guidelines for standardized analyses and best practice recommendations. The evolving landscape of precision oncology requires insights into critical factors supporting the sensitivity and reproducibility of clinical NGS assays for continued improvement in patient outcomes. Persistent development of robust reference materials, quantitative performance metrics, and actionable data analysis recommendations are needed. This series of SEQC2 studies serve to advance NGS-based assays for precision oncology and support regulatory science endeavors.

Next-Generation Molecular Residual Disease Assays: Do We Have the Tools to Evaluate Them Properly?

“…38 The ctDNA research community, including the US Foundation for the National Institutes of Health Biomarkers Consortium, 39 the Sequencing and Quality Control 2 project, 40 the Friends of Cancer Research ctDNA for Monitoring Treatment Response (ctMoniTR) project, 27 and most recently the EU Innovative Health Initiative GUIDE.MRD project, 41 have put forth, or are evaluating, several types of contrived reference materials including fragmented cell lines and oligonucleotides. 38,42,43 The use of these samples to assess ctDNA assay performance has worked well for assays examining genomic features (ie, somatic variants), but these samples do not carry the disease-specific methylation, fragmentome, or histonemodification features assessed by newer technologies, and they are not commutable to clinical samples (Fig 1A). However, clinical trial samples lack the required volume to perform multiple tests and are not usually consented for assay development.…”

Clinical Circulating Tumor DNA Testing for Precision Oncology

“…The Sequencing Quality Control Phase 2 (SEQC2) consortium organized by the FDA is an international group of members from academia, government, and industry (https://www.fda.gov/science-research/bioinformatics-tools/ microarraysequencing-quality-control-maqcseqc#MAQC_ IV). The SEQC2 Oncopanel Sequencing Working Group developed a translational scientific infrastructure to be applied for practices in precision oncology [69]. The Oncopanel Sequencing Working Group evaluated panels/assays, genomic regions, coverage, VAF ranges, and bioinformatics pipelines, using self-constructed reference samples.…”