Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

The PEACE consortium; The TRACERx consortium

doi:10.1038/nature22364

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

The PEACE consortium, The TRACERx consortium

Clinic of Radiology and Nuclear Medicine

1560 Citations (Scopus)

Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Original language	English
Journal	Nature
Volume	545
Issue number	7655
Pages (from-to)	446-451
Number of pages	6
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature22364
Publication status	Published - 26.04.2017

Funding

We acknowledge R. Macina for developing the collaboration between Natera and TRACERx. We thank S. Navarro and A. Tin for facilitating the PEACE ctDNA analysis. We thank the members of the TRACERx and PEACE consortia for participating in this study. C.S. is Royal Society Napier Research Professor. This work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202) and the Wellcome Trust (FC001169, FC001202). C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation and the European Research Council (THESEUS), and support was provided to C.S. by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Medicine Centre. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of the Francis Crick Institute. The TRACERx study (https://clinicaltrials.gov/ct2/show/NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). TRACERx is funded by Cancer Research UK (grant number C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. The PEACE study (https://clinicaltrials.gov/ct2/show/NCT03004755) is sponsored by University College London (UCL/13/0165) and has been approved by an independent Research Ethics Committee (13/LO/0972). PEACE is funded by Cancer Research UK (C416/A21999) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 9 Industry, Innovation, and Infrastructure

Research Areas and Centers

Academic Focus: Biomedical Engineering

Access to Document

10.1038/nature22364

Cite this

@article{15f544f2bcfa4a629a4ac7bac8dc3941,

title = "Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution",

abstract = "The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.",

author = "\{The PEACE consortium\} and \{The TRACERx consortium\} and Christopher Abbosh and Birkbak, \{Nicolai J.\} and Wilson, \{Gareth A.\} and Mariam Jamal-Hanjani and Tudor Constantin and Raheleh Salari and \{Le Quesne\}, John and Moore, \{David A.\} and Selvaraju Veeriah and Rachel Rosenthal and Teresa Marafioti and Eser Kirkizlar and Watkins, \{Thomas B.K.\} and Nicholas McGranahan and Sophia Ward and Luke Martinson and Joan Riley and Francesco Fraioli and \{Al Bakir\}, Maise and Eva Gr{\"o}nroos and Francisco Zambrana and Raymondo Endozo and Bi, \{Wenya Linda\} and Fennessy, \{Fiona M.\} and Nicole Sponer and Diana Johnson and Joanne Laycock and Seema Shafi and Justyna Czyzewska-Khan and Andrew Rowan and Tim Chambers and Nik Matthews and Samra Turajlic and Crispin Hiley and Lee, \{Siow Ming\} and Forster, \{Martin D.\} and Tanya Ahmad and Mary Falzon and Elaine Borg and David Lawrence and Martin Hayward and Shyam Kolvekar and Nikolaos Panagiotopoulos and Janes, \{Sam M.\} and Ricky Thakrar and Asia Ahmed and Fiona Blackhall and Yvonne Summers and Dina Hafez and Ashwini Naik",

note = "Funding Information: We acknowledge R. Macina for developing the collaboration between Natera and TRACERx. We thank S. Navarro and A. Tin for facilitating the PEACE ctDNA analysis. We thank the members of the TRACERx and PEACE consortia for participating in this study. C.S. is Royal Society Napier Research Professor. This work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202) and the Wellcome Trust (FC001169, FC001202). C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation and the European Research Council (THESEUS), and support was provided to C.S. by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Medicine Centre. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of the Francis Crick Institute. The TRACERx study (https://clinicaltrials.gov/ct2/show/NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). TRACERx is funded by Cancer Research UK (grant number C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. The PEACE study (https://clinicaltrials.gov/ct2/show/NCT03004755) is sponsored by University College London (UCL/13/0165) and has been approved by an independent Research Ethics Committee (13/LO/0972). PEACE is funded by Cancer Research UK (C416/A21999) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2017",

month = apr,

day = "26",

doi = "10.1038/nature22364",

language = "English",

volume = "545",

pages = "446--451",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7655",

}

TY - JOUR

T1 - Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

AU - The PEACE consortium

AU - The TRACERx consortium

AU - Abbosh, Christopher

AU - Birkbak, Nicolai J.

AU - Wilson, Gareth A.

AU - Jamal-Hanjani, Mariam

AU - Constantin, Tudor

AU - Salari, Raheleh

AU - Le Quesne, John

AU - Moore, David A.

AU - Veeriah, Selvaraju

AU - Rosenthal, Rachel

AU - Marafioti, Teresa

AU - Kirkizlar, Eser

AU - Watkins, Thomas B.K.

AU - McGranahan, Nicholas

AU - Ward, Sophia

AU - Martinson, Luke

AU - Riley, Joan

AU - Fraioli, Francesco

AU - Al Bakir, Maise

AU - Grönroos, Eva

AU - Zambrana, Francisco

AU - Endozo, Raymondo

AU - Bi, Wenya Linda

AU - Fennessy, Fiona M.

AU - Sponer, Nicole

AU - Johnson, Diana

AU - Laycock, Joanne

AU - Shafi, Seema

AU - Czyzewska-Khan, Justyna

AU - Rowan, Andrew

AU - Chambers, Tim

AU - Matthews, Nik

AU - Turajlic, Samra

AU - Hiley, Crispin

AU - Lee, Siow Ming

AU - Forster, Martin D.

AU - Ahmad, Tanya

AU - Falzon, Mary

AU - Borg, Elaine

AU - Lawrence, David

AU - Hayward, Martin

AU - Kolvekar, Shyam

AU - Panagiotopoulos, Nikolaos

AU - Janes, Sam M.

AU - Thakrar, Ricky

AU - Ahmed, Asia

AU - Blackhall, Fiona

AU - Summers, Yvonne

AU - Hafez, Dina

AU - Naik, Ashwini

N1 - Funding Information: We acknowledge R. Macina for developing the collaboration between Natera and TRACERx. We thank S. Navarro and A. Tin for facilitating the PEACE ctDNA analysis. We thank the members of the TRACERx and PEACE consortia for participating in this study. C.S. is Royal Society Napier Research Professor. This work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202) and the Wellcome Trust (FC001169, FC001202). C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation and the European Research Council (THESEUS), and support was provided to C.S. by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Medicine Centre. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of the Francis Crick Institute. The TRACERx study (https://clinicaltrials.gov/ct2/show/NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). TRACERx is funded by Cancer Research UK (grant number C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. The PEACE study (https://clinicaltrials.gov/ct2/show/NCT03004755) is sponsored by University College London (UCL/13/0165) and has been approved by an independent Research Ethics Committee (13/LO/0972). PEACE is funded by Cancer Research UK (C416/A21999) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. Publisher Copyright: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2017/4/26

Y1 - 2017/4/26

N2 - The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

AB - The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

UR - https://www.scopus.com/pages/publications/85019743651

U2 - 10.1038/nature22364

DO - 10.1038/nature22364

M3 - Journal articles

C2 - 28445469

AN - SCOPUS:85019743651

SN - 0028-0836

VL - 545

SP - 446

EP - 451

JO - Nature

JF - Nature

IS - 7655

ER -

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Abstract

Funding

UN SDGs

Research Areas and Centers

Access to Document

Other files and links

Fingerprint

Cite this