TY - JOUR
T1 - Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
AU - TRACERx Consortium
AU - Abbosh, Christopher
AU - Frankell, Alexander M.
AU - Harrison, Thomas
AU - Kisistok, Judit
AU - Garnett, Aaron
AU - Johnson, Laura
AU - Veeriah, Selvaraju
AU - Moreau, Mike
AU - Chesh, Adrian
AU - Chaunzwa, Tafadzwa L.
AU - Weiss, Jakob
AU - Schroeder, Morgan R.
AU - Ward, Sophia
AU - Grigoriadis, Kristiana
AU - Shahpurwalla, Aamir
AU - Litchfield, Kevin
AU - Puttick, Clare
AU - Biswas, Dhruva
AU - Karasaki, Takahiro
AU - Black, James R.M.
AU - Martínez-Ruiz, Carlos
AU - Bakir, Maise Al
AU - Pich, Oriol
AU - Watkins, Thomas B.K.
AU - Lim, Emilia L.
AU - Huebner, Ariana
AU - Moore, David A.
AU - Godin-Heymann, Nadia
AU - L’Hernault, Anne
AU - Bye, Hannah
AU - Odell, Aaron
AU - Roberts, Paula
AU - Gomes, Fabio
AU - Patel, Akshay J.
AU - Manzano, Elizabeth
AU - Hiley, Crispin T.
AU - Carey, Nicolas
AU - Riley, Joan
AU - Cook, Daniel E.
AU - Hodgson, Darren
AU - Stetson, Daniel
AU - Barrett, J. Carl
AU - Kortlever, Roderik M.
AU - Evan, Gerard I.
AU - Hackshaw, Allan
AU - Daber, Robert D.
AU - Shaw, Jacqui A.
AU - Van Loo, Peter
AU - Pan, Xiaoxi
AU - Yuan, Yinyin
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/20
Y1 - 2023/4/20
N2 - Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. 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 study2. 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.
AB - Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. 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 study2. 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.
UR - http://www.scopus.com/inward/record.url?scp=85152467768&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85152467768&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-05776-4
DO - 10.1038/s41586-023-05776-4
M3 - Article
C2 - 37055640
AN - SCOPUS:85152467768
SN - 0028-0836
VL - 616
SP - 553
EP - 562
JO - Nature
JF - Nature
IS - 7957
ER -