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Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. 2023
Christopher Abbosh, and
Alexander M Frankell, and
Thomas Harrison, and
Judit Kisistok, and
Aaron Garnett, and
Laura Johnson, and
Selvaraju Veeriah, and
Mike Moreau, and
Adrian Chesh, and
Tafadzwa L Chaunzwa, and
Jakob Weiss, and
Morgan R Schroeder, and
Sophia Ward, and
Kristiana Grigoriadis, and
Aamir Shahpurwalla, and
Kevin Litchfield, and
Clare Puttick, and
Dhruva Biswas, and
Takahiro Karasaki, and
James R M Black, and
Carlos Martínez-Ruiz, and
Maise Al Bakir, and
Oriol Pich, and
Thomas B K Watkins, and
Emilia L Lim, and
Ariana Huebner, and
David A Moore, and
Nadia Godin-Heymann, and
Anne L'Hernault, and
Hannah Bye, and
Aaron Odell, and
Paula Roberts, and
Fabio Gomes, and
Akshay J Patel, and
Elizabeth Manzano, and
Crispin T Hiley, and
Nicolas Carey, and
Joan Riley, and
Daniel E Cook, and
Darren Hodgson, and
Daniel Stetson, and
J Carl Barrett, and
Roderik M Kortlever, and
Gerard I Evan, and
Allan Hackshaw, and
Robert D Daber, and
Jacqui A Shaw, and
Hugo J W L Aerts, and
Abel Licon, and
Josh Stahl, and
Mariam Jamal-Hanjani, and
, and
Nicolai J Birkbak, and
Nicholas McGranahan, and
Charles Swanton
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. c.abbosh@ucl.ac.uk.
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
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Elizabeth Manzano, and
Crispin T Hiley, and
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Joan Riley, and
Daniel E Cook, and
Darren Hodgson, and
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J Carl Barrett, and
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Gerard I Evan, and
Allan Hackshaw, and
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Alexander M Frankell, and
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Tafadzwa L Chaunzwa, and
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Morgan R Schroeder, and
Sophia Ward, and
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Aamir Shahpurwalla, and
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Clare Puttick, and
Dhruva Biswas, and
Takahiro Karasaki, and
James R M Black, and
Carlos Martínez-Ruiz, and
Maise Al Bakir, and
Oriol Pich, and
Thomas B K Watkins, and
Emilia L Lim, and
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Nadia Godin-Heymann, and
Anne L'Hernault, and
Hannah Bye, and
Aaron Odell, and
Paula Roberts, and
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Joan Riley, and
Daniel E Cook, and
Darren Hodgson, and
Daniel Stetson, and
J Carl Barrett, and
Roderik M Kortlever, and
Gerard I Evan, and
Allan Hackshaw, and
Robert D Daber, and
Jacqui A Shaw, and
Hugo J W L Aerts, and
Abel Licon, and
Josh Stahl, and
Mariam Jamal-Hanjani, and
, and
Nicolai J Birkbak, and
Nicholas McGranahan, and
Charles Swanton
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Future oncology (London, England),
