Ultrasensitive ctDNA detection for preoperative disease stratification in early-stage lung adenocarcinoma
James R. Black, Gábor Bartha, Charles W. Abbott, Sean Michael Boyle, Takahiro Karasaki, Bailiang Li, Rui Chen, Jason Harris, Selvaraju Veeriah, Marzia Colopi, Maise Al Bakir, Wing Kin Liu, John Lyle, Fábio C. P. Navarro, Josette Northcott, Rachel Marty Pyke, Mark S. Hill, Kerstin Thol, Ariana Huebner, Chris Bailey, Emma Colliver, Carlos Martínez‐Ruiz, Kristiana Grigoriadis, Piotr Pawlik, David A. Moore, Daniele Marinelli, Oliver G. Shutkever, Cian Murphy, Monica Sivakumar, J.F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Mohamad Tufail, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Dean A. Fennell, Gurdeep Matharu, Ekaterini Boleti, Heather Cheyne, Mohammed Khalil, Shirley Richardson, Tracey Cruickshank, Gillian Price, Keith M. Kerr, Sarah Benafif, Jack French, Kayleigh Gilbert, Babu Naidu, Akshay J. Patel, Aya Osman, Carol Enstone, Gerald Langman, Helen Shackleford, Madava Djearaman, Salma Kadiri, Gary Middleton, Angela Leek, Jack Davies Hodgkinson, Nikki Totton, Ángeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato, António Paiva‐Correia, Juliette Novasio, Kendadai Rammohan, Leena Dennis Joseph, Paul Bishop, Rajesh Shah, Stuart Moss, Vijay Joshi, Philip Crosbie, Katherine D. Brown, Mathew Carter, Anshuman Chaturvedi, Pedro Oliveira, Colin R. Lindsay, Fiona Blackhall, Matthew Krebs, Yvonne Summers, Alexandra Clipson, Jonathan Tugwood, Alastair Kerr, Dominic G. Rothwell, Caroline Dive, Hugo J.W.L. Aerts, Roland F. Schwarz, Tom L. Kaufmann, Gareth A. Wilson, Rachel Rosenthal, Peter Van Loo, Nicolai J. Birkbak, Zoltán Szállási, Judit Kisistók, Mateo Sokač
Abstract
Circulating tumor DNA (ctDNA) detection can predict clinical risk in early-stage tumors. However, clinical applications are constrained by the sensitivity of clinically validated ctDNA detection approaches. NeXT Personal is a whole-genome-based, tumor-informed platform that has been analytically validated for ultrasensitive ctDNA detection at 1-3 ppm of ctDNA with 99.9% specificity. Through an analysis of 171 patients with early-stage lung cancer from the TRACERx study, we detected ctDNA pre-operatively within 81% of patients with lung adenocarcinoma (LUAD), including 53% of those with pathological TNM (pTNM) stage I disease. ctDNA predicted worse clinical outcome, and patients with LUAD with <80 ppm preoperative ctDNA levels (the 95% limit of detection of a ctDNA detection approach previously published in TRACERx) experienced reduced overall survival compared with ctDNA-negative patients with LUAD. Although prospective studies are needed to confirm the clinical utility of the assay, these data show that our approach has the potential to improve disease stratification in early-stage LUADs.