Tracking early lung cancer metastatic dissemination in TRACERx using ctDNAMore about Open Access at the Crick
Authors listChristopher Abbosh Alexander Frankell Thomas Harrison Judit Kisistok Aaron Garnett Laura Johnson Selvaraju Veeriah Mike Moreau Adrian Chesh Tafadzwa L Chaunzwa Jakob Weiss Morgan R Schroeder Sophie Ward Kristiana Grigoriadis Aamir Shahpurwalla Kevin Litchfield Clare Puttick Dhruva Biswas Takahiro Karasaki James RM Black Carlos Martínez-Ruiz Maise Al Bakir Oriol Pich Tom Watkins Emilia 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 Hiley Nicolas Carey Joan Riley Daniel E Cook Darren Hodgson Daniel Stetson J Carl Barrett Roderik M Kortlever Gerard Evan Allan Hackshaw Robert D Daber Jacqui A Shaw Hugo JWL Aerts Abel Licon Josh Stahl Mariam Jamal-Hanjani TRACERx Consortium Nicolai Birkbak Nicholas McGranahan Charles Swanton
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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.
Issue number 7957