Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
Christopher Abbosh, Alexander M. Frankell, Thomas Harrison, Judit Kisistók, Aaron T. 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. Black, Carlos 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 Kalavakur, Fábio 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, Gérard I. Evan, Allan Hackshaw, Robert Daber, Jacqui Shaw, Hugo J.W.L. Aerts, Abel Licon, Josh Stahl, Mariam Jamal‐Hanjani, J.F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Keng Ang, Mohamad Tufail, Mohammed Fiyaz Chowdhry, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Dean A. Fennell, Gurdeep Matharu, Lindsay Primrose, Ekaterini Boleti, Heather Cheyne, Mohammed S. Khalil, Shirley Richardson, Tracey Cruickshank, Gillian Price, Keith M. Kerr, Sarah Benafif, Kayleigh Gilbert, Babu Naidu, Aya Osman, Christer Lacson, Gerald Langman, Helen Shackleford, Madava Djearaman, Salma Kadiri, Gary Middleton, Angela Leek, Jack Davies Hodgkinson, Nicola Totten, Ángeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato, Helen Doran, Juliette Novasio, Kendadai Rammohan, Leena Dennis Joseph, Paul Bishop, Rajesh Shah, Stuart Moss, Vijay Joshi, Philip Crosbie
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. Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.