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%D 2025
%P 70-76
%V 31
%L discovery10205077
%I NATURE PORTFOLIO
%C United States
%T Ultrasensitive ctDNA detection for preoperative disease stratification in early-stage lung adenocarcinoma
%A James RM Black
%A Gabor Bartha
%A Charles W Abbott
%A Sean M Boyle
%A Takahiro Karasaki
%A Bailiang Li
%A Rui Chen
%A Jason Harris
%A Selvaraju Veeriah
%A Martina Colopi
%A Maise Al Bakir
%A Wing Kin Liu
%A John Lyle
%A Fabio CP Navarro
%A Josette Northcott
%A Rachel Marty Pyke
%A Mark S Hill
%A Kerstin Thol
%A Ariana Huebner
%A Chris Bailey
%A Emma C Colliver
%A Carlos Martinez-Ruiz
%A Kristiana Grigoriadis
%A Piotr Pawlik
%A David A Moore
%A Daniele Marinelli
%A Oliver G Shutkever
%A Cian Murphy
%A Monica Sivakumar
%A Jacqui A Shaw
%A Allan Hackshaw
%A Nicholas McGranahan
%A Mariam Jamal-Hanjani
%A Alexander M Frankell
%A Richard O Chen
%A Charles Swanton
%J Nature Medicine
%X 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.