Evaluation of cell-free DNA approaches for multi-cancer early detection.

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.

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Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests A.J., O.V., E.H., J.F.B., S.G., Q.L., N.Z., E.T.F., K.N.K., H.A., C.B., D.C., K.D., S.F., C.H., R.J., B.J., S.T., C.M., V.D., J.N., O.S., E.S., A.S., S.S., K.K.S., V.N., A.P.F., T.C.C., S.B., N.H., M.D., Z.D., and M.P.H. are employees of GRAIL, LLC, with equity in Illumina, Inc. C.M. also holds stock in Novartis, Clovis, Cara, Gilead, and Bluebird. M.C.L. is an uncompensated consultant for GRAIL, LLC. The Mayo Clinic was compensated for M.C.L.’s and D.D.T.’s advisory board activities for GRAIL, LLC. E.A.K. is a consultant for GRAIL, LLC. D.A.R. is a consultant for Ipsen. M.A.S. is a consultant for Celgene, Millennium, and Syros Pharmaceuticals. A.M.A. was previously employed by GRAIL, LLC; has equity in Illumina, Inc.; is currently employed by Illumina, Inc.; and is an advisor to and an equity holder in Foresite Labs and Myst Therapeutics. M.V.S. is an employee of and holds stock in McKesson Corporation, and is a clinical adviser for GRAIL, LLC. D.A.B. is a co-owner of Berry Consultants, LLC. A.H.B. is a consultant for Pfizer, Merck, Bayer, and Astellas Pharmaceuticals. C.S. holds stock in Illumina, Inc., Epic Biosciences, and Apogen Biotech; receives grants from Pfizer and AstraZeneca; receives honoraria or consultant fees from Roche Ventana, Celgene, Pfizer, Novartis, Genentech, and BMS; and is a co-founder of Achilles Therapeutics. S.G., O.V., A.P.F., A.J., K.D., V.N., J.F.B., C.M., E.H., Q.L., N.Z., P.F., and O.S. are inventors on pending patent applications related to this work, for which GRAIL, LLC, has ownership rights. GRAIL, LLC, a subsidiary of Illumina, Inc., is currently held separate from Illumina, Inc., under the terms of the Interim Measures Order of the European Commission dated October 29, 2021. C.S. recieved grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc), and Ono Pharmaceutical; is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board (SAB); received consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Centre – Shanghai, Metabomed, and the Sarah Cannon Research Institute; received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Illumina, and Roche-Ventana; had stock options in Apogen Biotechnologies and GRAIL until June 2021, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and Achilles Therapeutics; and is a co-founder of Achilles Therapeutics; holds patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289), targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), and identifying patients who respond to cancer treatment (PCT/GB2018/051912); holds US patent relating to detecting tumour mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1); and holds both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C.S. is a Royal Society Napier Research Professor (RSRP\R\210001) and has received funding from the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041), and the Wellcome Trust (CC2041); Cancer Research UK (TRACERx [C11496/A17786], PEACE [C416/A21999], and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US) (BCRF-22-157); Cancer Research UK Early Detection and Diagnosis Primer Award (Grant EDDPMA-Nov21/100034); The Mark Foundation for Cancer Research Aspire Award (Grant 21-029-ASP); Stand Up To Cancer-LUNGevity American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17); and an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 835297).