Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Christopher Abbosh*, Alexander M. Frankell, Thomas Harrison, Judit Kisistok, Aaron Garnett, Laura Johnson, Selvaraju Veeriah, Mike Moreau, Adrian Chesh, Tafadzwa L. Chaunzwa, Jakob Weiss, Morgan R. Schroeder, Sophia Ward, Kristiana Grigoriadis, Aamir Shahpurwalla, Kevin Litchfield, Clare Puttick, Dhruva Biswas, Takahiro Karasaki, James R.M. BlackCarlos Martínez-Ruiz, Maise Al Bakir, Oriol Pich, Thomas B.K. Watkins, Emilia L. Lim, Ariana Huebner, David A. Moore, Nadia Godin-Heymann, Anne L’Hernault, Hannah Bye, Aaron Odell, Paula Roberts, Fabio Gomes, Akshay J. Patel, Elizabeth Manzano, Crispin T. Hiley, Nicolas Carey, Joan Riley, Daniel E. Cook, Darren Hodgson, Daniel Stetson, J. Carl Barrett, Roderik M. Kortlever, Gerard I. Evan, Allan Hackshaw, Robert D. Daber, Nicolai J. Birkbak, TRACERx Consortium

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

109 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalNature
Volume616
Issue7957
Pages (from-to)553-562
Number of pages10
ISSN0028-0836
DOIs
Publication statusPublished - Apr 2023

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