Abstract
Multiplex somatic testing has emerged as a strategy to test patients with advanced cancer. We demonstrate our analytic validation approach for a gene hotspot panel and real-time prospective clinical application for any cancer type. The TruSight Tumor 26 assay amplifies 85 somatic hotspot regions across 26 genes. Using cell line and tumor mixes, we observed that 100% of the 14,715 targeted bases had at least 1000x raw coverage. We determined the sensitivity (100%, 95% CI: 96-100%), positive predictive value (100%, 95% CI: 96-100%), reproducibility (100% concordance), and limit of detection (3% variant allele frequency at 1000x read depth) of this assay to detect single nucleotide variants and small insertions and deletions. Next, we applied the assay prospectively in a clinical tumor sequencing study to evaluate 174 patients with metastatic or advanced cancer, including frozen tumors, formalin-fixed tumors, and enriched peripheral blood mononuclear cells in hematologic cancers. We reported one or more somatic mutations in 89 (53%) of the sequenced tumors (167 passing quality filters). Forty-three of these patients (26%) had mutations that would enable eligibility for targeted therapies. This study demonstrates the validity and feasibility of applying TruSight Tumor 26 for pan-cancer testing using multiple specimen types.
Highlights
Real-time genomic testing for patients with cancer is central to identifying actionable somatic alterations that can guide clinical decision-making for novel therapies in clinical trials [1]
Given the volume of testing and results that require interpretation, we utilized a curated database, Cancer Driver Log (CanDL) to support rapid clinical interpretation of somatic results and to flag clinically relevant mutations [5].This study demonstrates the feasibility of obtaining research tumor biopsies in realtime for clinical care and the potential impact of targeted genomic testing on clinical decision-making
All single nucleotide variants (SNVs) and indels previously reported in the Cancer Cell Line Encyclopedia (CCLE) or the Catalogue of Somatic Mutations in Cancer (COSMIC) databases that were within the TruSight Tumor 26 (TST) targeted regions were detected, and additional variants identified by TST were Sanger sequenced to confirm their presence
Summary
Real-time genomic testing for patients with cancer is central to identifying actionable somatic alterations that can guide clinical decision-making for novel therapies in clinical trials [1]. Phase II clinical trials with over 30,000 patients illustrates that biomarker-driven selection of personalized therapies results in significantly improved objective response rates, progression-free survival, and overall survival compared to non-personalized therapies [2].To enable ongoing drug development in trials that utilize such predictive www.impactjournals.com/oncotarget biomarkers, genomic testing strategies ideally should be cost-effective, have a rapid turnaround time, be applicable to multiple sample types, and meet common laboratory standards for clinical decision-making. To achieve these goals, diagnostic laboratories are implementing multi‐gene panels on generation sequencing platforms. These sample mixes were used to assess the sensitivity, positive predictive value (PPV), precision, and limit of detection of the TST assay to detect single nucleotide variants (SNVs) and small insertions and deletions (indels)
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