Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

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Item Type:	Article
Title:	Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
Creators Name:	Abbosh, C., Frankell, A.M., Harrison, T., Kisistok, J., Garnett, A., Johnson, L., Veeriah, S., Moreau, M., Chesh, A., Chaunzwa, T.L., Weiss, J., Schroeder, M.R., Ward, S., Grigoriadis, K., Shahpurwalla, A., Litchfield, K., Puttick, C., Biswas, D., Karasaki, T., Black, J.R.M., Martínez-Ruiz, C., Bakir, M.A.l., Pich, O., Watkins, T.B.K., Lim, E.L., Huebner, A., Moore, D.A., Godin-Heymann, N., L'Hernault, A., Bye, H., Odell, A., Roberts, P., Gomes, F., Patel, A.J., Manzano, E., Hiley, C.T., Carey, N., Riley, J., Cook, D.E., Hodgson, D., Stetson, D., Barrett, J.C., Kortlever, R.M., Evan, G.I., Hackshaw, A., Daber, R.D., Shaw, J.A., Aerts, H.J.W.L., Licon, A., Stahl, J., Jamal-Hanjani, M., Birkbak, N.J., McGranahan, N. and Swanton, C.
Abstract:	Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy. 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. 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.
Keywords:	Circulating Tumor DNA, Cohort Studies, Liquid Biopsy, Local Neoplasm Recurrence, Lung Neoplasms, Mutation, Neoplasm Metastasis, Non-Small-Cell Lung Carcinoma, Phylogeny, Small Cell Lung Carcinoma, Tumor Biomarkers
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	616
Number:	7957
Page Range:	553-562
Date:	20 April 2023
Additional Information:	Tom L. Kaufmann (19184) is a member of the TRACERx Consortium. - Copyright © 2023. The Author(s).
Official Publication:	https://doi.org/10.1038/s41586-023-05776-4
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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