Ultrasensitive ctDNA detection for preoperative disease stratification in early-stage lung adenocarcinoma
Authors: James R. M. Black, Gabor Bartha, Charles W. Abbott, Sean M. Boyle, Takahiro Karasaki, Bailiang Li, Rui Chen, Jason Harris, Selvaraju Veeriah, Martina 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 C. Colliver, Carlos Martínez-Ruiz, Kristiana Grigoriadis, Piotr Pawlik, David A. Moore, Daniele Marinelli, Oliver G. Shutkever, Cian Murphy, Monica Sivakumar, Jason 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, Nicola Totton, Angeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato, Antonio Paiva-Correia, Juliette Novasio, Kendadai Rammohan, Leena Joseph, Paul Bishop, Rajesh Shah, Stuart Moss, Vijay Joshi, Philip A. J. Crosbie, Katherine D. Brown, Mathew Carter, Anshuman Chaturvedi, Pedro Oliveira, Colin R. Lindsay, Fiona H. Blackhall, Matthew G. Krebs, Yvonne Summers, Alexandra Clipson, Jonathan Tugwood, Alastair Kerr, Dominic G. Rothwell, Caroline Dive, Hugo JWL Aerts, Roland F. Schwarz, Tom L. Kaufmann, Gareth A. Wilson, Rachel Rosenthal, Peter Van Loo, Nicolai J. Birkbak, Zoltan Szallasi, Judit Kisistok, Mateo Sokac, Roberto Salgado, Miklos Diossy, Jonas Demeulemeester, Abigail Bunkum, Angela Dwornik, Alastair Magness, Andrew J. Rowan, Angeliki Karamani, Antonia Toncheva, Benny Chain, Carla Castignani, Christopher Abbosh, Clare Puttick, Clare E. Weeden, Claudia Lee, Corentin Richard, Crispin T. Hiley, Cristina Naceur-Lombardelli, David R. Pearce, Despoina Karagianni, Dhruva Biswas, Dina Levi, Elizabeth Larose Cadieux, Emilia L. Lim, Emma Nye, Eva Grönroos, Felip Gálvez-Cancino, Francisco Gimeno-Valiente, George Kassiotis, Georgia Stavrou, Gerasimos-Theodoros Mastrokalos, Helen L. Lowe, Ignacio Garcia Matos, Imran Noorani, Jacki Goldman, James L. Reading, Jayant K. Rane, Jerome Nicod, John A. Hartley, Karl S. Peggs, Katey S. S. Enfield, Kayalvizhi Selvaraju, Kevin Litchfield, Kevin W. Ng, Kezhong Chen, Krijn Dijkstra, Krupa Thakkar, Leah Ensell, Mansi Shah, Maria Litovchenko, Mariana Werner Sunderland, Matthew R. Huska, Michelle Dietzen, Michelle M. Leung, Mickael Escudero, Mihaela Angelova, Miljana Tanić, Nnennaya Kanu, Olga Chervova, Olivia Lucas, Oriol Pich, Othman Al-Sawaf, Paulina Prymas, Philip Hobson, Richard Kevin Stone, Robert Bentham, Robert E. Hynds, Roberto Vendramin, Sadegh Saghafinia, Samuel Gamble, Seng Kuong Anakin Ung, Sergio A. Quezada, Sharon Vanloo, Simone Zaccaria, Sonya Hessey, Sophia Ward, Sian Harries, Stefan Boeing, Stephan Beck, Supreet Kaur Bola, Tamara Denner, Teresa Marafioti, Thomas B. K. Watkins, Thomas Patrick Jones, Victoria Spanswick, Vittorio Barbè, Wei-Ting Lu, William Hill, Yin Wu, Yutaka Naito, Zoe Ramsden, Catarina Veiga, Gary Royle, Charles-Antoine Collins-Fekete, Francesco Fraioli, Paul Ashford, Martin D. Forster, Siow Ming Lee, Elaine Borg, Mary Falzon, Dionysis Papadatos-Pastos, James Wilson, Tanya Ahmad, Alexander James Procter, Asia Ahmed, Magali N. Taylor, Arjun Nair, David Lawrence, Davide Patrini, Neal Navani, Ricky M. Thakrar, Sam M. Janes, Emilie Martinoni Hoogenboom, Fleur Monk, James W. Holding, Junaid Choudhary, Kunal Bhakhri, Marco Scarci, Pat Gorman, Reena Khiroya, Robert CM Stephens, Yien Ning Sophia Wong, Zoltan Kaplar, Steve Bandula, Anne-Marie Hacker, Abigail Sharp, Sean Smith, Harjot Kaur Dhanda, Camilla Pilotti, Rachel Leslie, Anca Grapa, Hanyun Zhang, Khalid AbdulJabbar, Xiaoxi Pan, Yinyin Yuan, David Chuter, Mairead MacKenzie, Serena Chee, Aiman Alzetani, Judith Cave, Jennifer Richards, Eric Lim, Paulo De Sousa, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Harshil Bhayani, Lyn Ambrose, Anand Devaraj, Hema Chavan, Sofina Begum, Silviu I. Buderi, Daniel Kaniu, Mpho Malima, Sarah Booth, Andrew G. Nicholson, Nadia Fernandes, Pratibha Shah, Chiara Proli, Madeleine Hewish, Sarah Danson, Michael J. Shackcloth, Lily Robinson, Peter Russell, Kevin G. Blyth, Andrew Kidd, Craig Dick, John Le Quesne, Alan Kirk, Mo Asif, Rocco Bilancia, Nikos Kostoulas, Mathew Thomas, Jacqui A. Shaw, Allan Hackshaw, Nicholas McGranahan, Mariam Jamal-Hanjani, Alexander M. Frankell, Richard O. Chen, Charles Swanton
Journal: Nature Medicine (2025)

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 &lt;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.