A Concordance Study Among 26 NGS Laboratories Participating in the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) Clinical Trial

06/04/2025

A Concordance Study Among 26 NGS Laboratories Participating in the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) Clinical Trial

Clinical Cancer Research

Authors Linda K. Zane, Laura M. Yee, Ting-Chia Chang, Jeffrey Sklar, Guangxiao Yang, Jia Di Wen, Peining Li, Robin Harrington, David J. Sims, Kneshay Harper, Jeffrey M. Trent, Janine R. LoBello, Szabolcs Szelinger, Kasey Benson, Jia Zeng, Kelsey Poorman, Danbin Xu, Garrett M. Frampton, Dean C. Pavlick, Vincent A. Miller, Bevan Tandon, Wojciech Swat, Lawrence Weiss, Vincent Anthony. Funari, Jeffrey M. Conroy, James L. Prescott, Pranil K. Chandra, Charles Ma, Kristen J. Champion, Gregory X. Baschkopf, Yuri A. Fesko, Tracey Allen K. Freitas, Scott A. Tomlins, Daniel H. Hovelson, Kevin White, Shelly Sorrells, Robert Tell, Nike Beaubier, David King, Lei Li, Kevin Kelly, Jasmina Uvalic, Bridgette Meyers, Ravindra Kolhe, Neal I. Lindeman, Michele Baltay, Lynette M. Sholl, Jean Lopategui, Eric Vail, Wenjuan Zhang, Milhan Telatar, Michelle Afkhami, Susan J. Hsiao, Mahesh M. Mansukhani, Emily Adams, LiQun Jiang, Kenneth D. Aldape, Mark Raffeld, Liqiang Xi, Henning Stehr, Jeremy P. Segal, Dara L. Aisner, Kurtis D. Davies, Noah A. Brown, Robert J. Livingston, Eric Q. Konnick, Wei Song, James P. Solomon, Zenta Walther, Lisa M. McShane, Lyndsay N. Harris, Alice P. Chen, Gregory J. Tsongalis, Stanley R. Hamilton, Keith T. Flaherty, Peter J. O'Dwyer, Barbara A. Conley, David R. Patton, A. John Iafrate, P. Mickey Williams, James V. Tricoli, Chris Karlovich

Purpose: NCI selected a network of CLIA-certified laboratories performing routine NGS tumor testing to identify patients for the NCI-MATCH trial. This large network provided a unique opportunity to compare variant detection and reporting between a wide range of testing platforms.

Experimental Design: Twenty-eight NGS assays from 26 laboratories within the NCI-MATCH network, including the NCI-MATCH central laboratory (CL) and 11 commercial and 14 academic designated laboratories (DL), were used for this study. DNA from 8 cell lines and 2 clinical samples were sequenced. Pairwise comparisons in variant detection and reporting between each DL and CL were performed for SNV, Indel, and CNV variant classes.

Results: We observed high concordance in variant detection between CL and DL for SNVs and Indels (Average Positive Agreement, APA>95.4% for all pairwise comparisons) but lower concordance for variant reporting after analysis pipeline filtering. We observed much higher agreement between CL and assays using amplification as the target enrichment method (84.2%<APA≤95.7%, average APA=88.7%) than with other assays using hybridization capture (69.7%<APA≤93.8%, average APA=77.4%) due to blacklisting of actionable variants in low complexity regions. For CNV reporting, we observed high agreement (APA>82%) except between CL and 2 assays (APA=76.9 and 71.4%) due to differences in estimation of copy numbers. Notably, for all variants, differences in variant interpretation also contributed to reporting discrepancies.

Conclusions: This study indicates that different NGS tumor profiling tests currently in widespread clinical use achieve high concordance between assays in variant detection. For variant reporting, observed discrepancies are mainly introduced during the bioinformatics analysis.

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