Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction

James R M Black¹, Takahiro Karasaki², Charles W Abbott³, Bailiang Li³, Selvaraju Veeriah¹, Maise Al Bakir⁴, Wing Kin Liu⁵, Ariana Huebner¹, Carlos Martínez-Ruiz¹, Piotr Pawlik⁶, David A Moore⁷, Daniele Marinelli⁸, Oliver Shutkever⁹, Cian Murphy¹, Lydia Y Liu¹, Charlotte Grieco¹, Karen Grimes¹⁰, Fabio C P Navarro³, Rachel Marty Pyke³, Gabor Bartha³, Kathleen C Keough³, Steven Dea³, Neeraja Ravi³, John Lyle³, Jason Harris³, Katherine D Brown¹¹, Fiona H Blackhall¹¹, Fatemah Hassani¹², Dean A Fennell¹³, Nicholas McGranahan¹⁰, Jacqui A Shaw¹⁴, Christopher Abbosh¹⁵; TRACERx Consortium; Allan Hackshaw¹⁶, Mariam Jamal-Hanjani¹⁷, Alexander M Frankell¹⁸, Sean M Boyle³, Richard O Chen³, Charles Swanton¹⁹

Affiliations

¹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
² Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ Personalis Inc., Fremont, CA, USA.
⁴ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK.
⁵ Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
⁶ Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
⁷ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK.
⁸ Department of Experimental Medicine, Sapienza University, Rome, Italy.
⁹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
¹⁰ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
¹¹ The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, The University of Manchester, Manchester, UK.
¹² University Hospitals of Leicester NHS Trust, Leicester, UK.
¹³ University Hospitals of Leicester NHS Trust, Leicester, UK; University of Leicester, Leicester, UK.
¹⁴ University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Leicester, UK.
¹⁵ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; AstraZeneca, Cambridge, UK.
¹⁶ Cancer Research UK, UCL Clinical Trials Centre, London, UK.
¹⁷ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
¹⁸ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Early Cancer Institute, University of Cambridge, Cambridge, UK.
¹⁹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK. Electronic address: charles.swanton@crick.ac.uk.

PMID: 41205598
DOI: 10.1016/j.cell.2025.10.020

Free article

Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction

James R M Black et al. Cell. 2025.

Free article

. 2025 Nov 7:S0092-8674(25)01192-4.

doi: 10.1016/j.cell.2025.10.020. Online ahead of print.

Authors

Affiliations

¹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
² Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ Personalis Inc., Fremont, CA, USA.
⁴ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK.
⁵ Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
⁶ Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
⁷ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK.
⁸ Department of Experimental Medicine, Sapienza University, Rome, Italy.
⁹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
¹⁰ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
¹¹ The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, The University of Manchester, Manchester, UK.
¹² University Hospitals of Leicester NHS Trust, Leicester, UK.
¹³ University Hospitals of Leicester NHS Trust, Leicester, UK; University of Leicester, Leicester, UK.
¹⁴ University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Leicester, UK.
¹⁵ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; AstraZeneca, Cambridge, UK.
¹⁶ Cancer Research UK, UCL Clinical Trials Centre, London, UK.
¹⁷ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
¹⁸ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Early Cancer Institute, University of Cambridge, Cambridge, UK.
¹⁹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK. Electronic address: charles.swanton@crick.ac.uk.

PMID: 41205598
DOI: 10.1016/j.cell.2025.10.020

Abstract

Biomarkers accurately informing prognostic assessment and therapeutic strategy are critical for improving patient outcome in oncology. Here, we apply a whole-genome, tumor-informed circulating tumor DNA (ctDNA) detection approach to address this challenge, leveraging 1,800 variants across 2,994 plasma samples from 431 patients with non-small cell lung cancer (NSCLC) from the TRACERx study. We show that ultrasensitive ctDNA detection below 80 parts per million both pre- and postoperatively is highly prognostic, and combinatorial analysis of the pre- and postoperative ctDNA status identifies an intermediate risk group, improving disease stratification. ctDNA kinetics demonstrate clinical utility during adjuvant therapy, where patients that "clear" ctDNA during adjuvant therapy experience improved outcomes. Moreover, characterization of patterns in postoperative ctDNA kinetics reveals insights into the timing, risk, and anatomical pattern of relapses. By incorporating longitudinal ultrasensitive ctDNA detection, we propose a refined schema for guiding the stratification and treatment recommendations in early stage NSCLC.

Keywords: circulating tumor DNA; liquid biopsy; molecular residual disease; non-small cell lung cancer; prognostic classification; therapy response prediction/monitoring.

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Conflict of interest statement

Declaration of interests M.A.B. has consulted for Achilles Therapeutics. D.A.M. reports speaker fees from AstraZeneca, Eli Lilly, BMS, and Takeda; consultancy fees from AstraZeneca, Thermo Fisher, Takeda, Amgen, Janssen, MIM Software, Bristol Myers Squibb, and Eli Lilly; and educational support from Takeda and Amgen. M.J.-H. has consulted for and is a member of the Achilles Therapeutics scientific advisory board and steering committee and has received speaker honoraria from Pfizer, Astex Pharmaceuticals, and Oslo Cancer Cluster. N.M. has received consultancy fees and has stock options in Achilles Therapeutics. C.A. reports employment and stock ownership at AstraZeneca and prior leadership and consulting roles at SAGA Diagnostics (Chief Medical Officer to Aug 2024). C.S. acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Invitae (previously Archer Dx Inc.—collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, and Personalis. He is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board. He was Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and the Steering Committee Chair. C.S. is a paid member of the board for Bicycle Therapeutics and Chair of the Clinical Advisory Group. He receives consultant fees from Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre—Shanghai, Relay Therapeutics (SAB member), Saga Diagnostics (SAB member), and Sarah Cannon Research Institute. He previously received consultant fees from Achilles Therapuetics. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, and Pfizer. C.S. has equity in Bicycle Therapeutics; stock options in Relay Therapeutics, Saga Diagnostics, and Bicycle Therapeutics; and has previously held stock and was co-founder of Achilles Therapeutics. G.B., C.W.A., S.M.B., J.H., B.L., J.L., F.C.P.N., R.M.P., S.D., N.R., K.C.K., and R.O.C. are employees and stockholders of Personalis Inc. A.M.F. is listed as a co-inventor on a patent application to determine methods and systems for tumor monitoring (PCT/EP2022/077987; Methods and systems for tumor monitoring). S.V. is a co-inventor to a patent of methods for detecting molecules in a sample (US patent no. 10578620; Methods for detecting molecules in a sample). M.J.-H. is listed as a co-inventor on a European patent application relating to methods to detect lung cancer (PCT/US2017/028013; Methods for lung cancer detection); this patent has been licensed to commercial entities and, under terms of employment, M.J.-H. is due a share of any revenue generated from such license(s). N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/059401; Method for treating cancer), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471; “Immune checkpoint intervention” in cancer), determining HLA LOH (PCT/GB2018/052004; Analysis of HLA alleles in tumors and the uses thereof), and predicting survival rates of patients with cancer (PCT/GB2020/050221; Method of predicting survival rates for cancer patients). C.A. is a named inventor on a patent application to determine methods and systems for tumor monitoring (PCT/EP2022/077987). C.S. and C.A. declare a patent application for methods to lung cancer (PCT/US2017/028013); targeting neoantigens (PCT/EP2016/059401); identifying patent response to immune checkpoint blockade (PCT/EP2016/071471); methods for lung cancer detection (US20190106751A1); identifying patients who respond to cancer treatment (PCT/GB2018/051912); determining HLA LOH (PCT/GB2018/052004); predicting survival rates of patients with cancer (PCT/GB2020/050221); methods and systems for tumor monitoring (PCT/EP2022/077987); and analysis of HLA alleles transcriptional deregulation (PCT/EP2023/059039). C.S. and C.A. are inventors on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumor recurrence. This patent has been licensed to a commercial entity, and under their terms of employment, C.S. and C.A. are due a revenue share of any revenue generated from such license(s).

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Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction

Affiliations

Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction

Authors

Affiliations

Abstract

Conflict of interest statement

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