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Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.

Christopher AbboshAlexander M FrankellThomas HarrisonJudit KisistokAaron GarnettLaura JohnsonSelvaraju VeeriahMike MoreauAdrian CheshTafadzwa L ChaunzwaJakob WeissMorgan R SchroederSophia WardKristiana GrigoriadisAamir ShahpurwallaKevin LitchfieldClare PuttickDhruva BiswasTakahiro KarasakiJames R M BlackCarlos Martínez-RuizMaise Al BakirOriol PichThomas B K WatkinsEmilia L LimAriana HuebnerDavid Allan MooreNadia Godin-HeymannAnne L'HernaultHannah ByeAaron OdellPaula RobertsFabio GomesAkshay J PatelElizabeth ManzanoCrispin T HileyNicolas CareyJoan RileyDaniel E CookDarren HodgsonDaniel StetsonJ Carl BarrettRoderik M KortleverGerard I EvanAllan HackshawRobert D DaberJacqueline A ShawHugo J W L AertsAbel LiconJosh StahlMariam Jamal-Hanjaninull nullNicolai Juul BirkbakNicholas McGranahanCharles Swanton
Published in: Nature (2023)
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy 1 . 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 study 2 . 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.
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