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