Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Christopher Abbosh; Alexander M. Frankell; Thomas Harrison; Judit Kisistok; Aaron Garnett; Laura Johnson; Selvaraju Veeriah; Mike Moreau; Adrian Chesh; Tafadzwa L. Chaunzwa; Jakob Weiss; Morgan R. Schroeder; Sophia Ward; Kristiana Grigoriadis; Aamir Shahpurwalla; Kevin Litchfield; Clare Puttick; Dhruva Biswas; Takahiro Karasaki; James R.M. Black; Carlos Martínez-Ruiz; Maise Al Bakir; Oriol Pich; Thomas B.K. Watkins; Emilia L. Lim; Ariana Huebner; David A. Moore; Nadia Godin-Heymann; Anne L’Hernault; Hannah Bye; Aaron Odell; Paula Roberts; Fabio Gomes; Akshay J. Patel; Elizabeth Manzano; Crispin T. Hiley; Nicolas Carey; Joan Riley; Daniel E. Cook; Darren Hodgson; Daniel Stetson; J. Carl Barrett; Roderik M. Kortlever; Gerard I. Evan; Allan Hackshaw; Robert D. Daber; Nicolai J. Birkbak; TRACERx Consortium

doi:10.1038/s41586-023-05776-4

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Christopher Abbosh^*, Alexander M. Frankell, Thomas Harrison, Judit Kisistok, Aaron Garnett, Laura Johnson, Selvaraju Veeriah, Mike Moreau, Adrian Chesh, Tafadzwa L. Chaunzwa, Jakob Weiss, Morgan R. Schroeder, Sophia Ward, Kristiana Grigoriadis, Aamir Shahpurwalla, Kevin Litchfield, Clare Puttick, Dhruva Biswas, Takahiro Karasaki, James R.M. BlackCarlos Martínez-Ruiz, Maise Al Bakir, Oriol Pich, Thomas B.K. Watkins, Emilia L. Lim, Ariana Huebner, David A. Moore, Nadia Godin-Heymann, Anne L’Hernault, Hannah Bye, Aaron Odell, Paula Roberts, Fabio Gomes, Akshay J. Patel, Elizabeth Manzano, Crispin T. Hiley, Nicolas Carey, Joan Riley, Daniel E. Cook, Darren Hodgson, Daniel Stetson, J. Carl Barrett, Roderik M. Kortlever, Gerard I. Evan, Allan Hackshaw, Robert D. Daber, Nicolai J. Birkbak, TRACERx Consortium

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

109 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nature
Volume	616
Issue	7957
Pages (from-to)	553-562
Number of pages	10
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-023-05776-4
Publication status	Published - Apr 2023

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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., ... TRACERx Consortium (2023). Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature, 616(7957), 553-562. https://doi.org/10.1038/s41586-023-05776-4

@article{077da039bbe44c248e7b7e2452fef393,

title = "Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA",

abstract = "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.",

author = "Christopher Abbosh and Frankell, {Alexander M.} and Thomas Harrison and Judit Kisistok and Aaron Garnett and Laura Johnson and Selvaraju Veeriah and Mike Moreau and Adrian Chesh and Chaunzwa, {Tafadzwa L.} and Jakob Weiss and Schroeder, {Morgan R.} and Sophia Ward and Kristiana Grigoriadis and Aamir Shahpurwalla and Kevin Litchfield and Clare Puttick and Dhruva Biswas and Takahiro Karasaki and Black, {James R.M.} and Carlos Mart{\'i}nez-Ruiz and Bakir, {Maise Al} and Oriol Pich and Watkins, {Thomas B.K.} and Lim, {Emilia L.} and Ariana Huebner and Moore, {David A.} and Nadia Godin-Heymann and Anne L{\textquoteright}Hernault and Hannah Bye and Aaron Odell and Paula Roberts and Fabio Gomes and Patel, {Akshay J.} and Elizabeth Manzano and Hiley, {Crispin T.} and Nicolas Carey and Joan Riley and Cook, {Daniel E.} and Darren Hodgson and Daniel Stetson and Barrett, {J. Carl} and Kortlever, {Roderik M.} and Evan, {Gerard I.} and Allan Hackshaw and Daber, {Robert D.} and Mateo Sokac and James Wilson and Asia Ahmed and Birkbak, {Nicolai J.} and {TRACERx Consortium}",

year = "2023",

month = apr,

doi = "10.1038/s41586-023-05776-4",

language = "English",

volume = "616",

pages = "553--562",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7957",

}

Abbosh, C, Frankell, AM, Harrison, T, Kisistok, J, Garnett, A, Johnson, L, Veeriah, S, Moreau, M, Chesh, A, Chaunzwa, TL, Weiss, J, Schroeder, MR, Ward, S, Grigoriadis, K, Shahpurwalla, A, Litchfield, K, Puttick, C, Biswas, D, Karasaki, T, Black, JRM, Martínez-Ruiz, C, Bakir, MA, Pich, O, Watkins, TBK, Lim, EL, Huebner, A, Moore, DA, Godin-Heymann, N, L’Hernault, A, Bye, H, Odell, A, Roberts, P, Gomes, F, Patel, AJ, Manzano, E, Hiley, CT, Carey, N, Riley, J, Cook, DE, Hodgson, D, Stetson, D, Barrett, JC, Kortlever, RM, Evan, GI, Hackshaw, A, Daber, RD, Birkbak, NJ & TRACERx Consortium 2023, 'Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA', Nature, vol. 616, no. 7957, pp. 553-562. https://doi.org/10.1038/s41586-023-05776-4

TY - JOUR

T1 - Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

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 - Sokac, Mateo

AU - Wilson, James

AU - Ahmed, Asia

AU - Birkbak, Nicolai J.

AU - TRACERx Consortium

PY - 2023/4

Y1 - 2023/4

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.

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U2 - 10.1038/s41586-023-05776-4

DO - 10.1038/s41586-023-05776-4

M3 - Journal article

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SN - 0028-0836

VL - 616

SP - 553

EP - 562

JO - Nature

JF - Nature

IS - 7957

ER -

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

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