The evolution of non-small cell lung cancer metastases in TRACERx

Maise Al Bakir, Ariana Huebner, Carlos Martínez-Ruiz, Kristiana Grigoriadis, Thomas B. K. Watkins, Oriol Pich, David A. Moore, Selvaraju Veeriah, Sophia Ward, Joanne Laycock, Diana Johnson, Andrew Rowan, Maryam Razaq, Mita Akther, Cristina Naceur-Lombardelli, Paulina Prymas, Antonia Toncheva, Sonya Hessey, Michelle Dietzen, Emma Colliver, Alexander M. Frankell, Abigail Bunkum, Emilia L. Lim, Takahiro Karasaki, Christopher Abbosh, Crispin T. Hiley, Mark S. Hill, Daniel E. Cook, Gareth A. Wilson, Roberto Salgado, Emma Nye, Richard Kevin Stone, Dean A. Fennell, Gillian Price, Keith M. Kerr, Babu Naidu, Gary Middleton, Yvonne Summers, Colin R. Lindsay, Fiona H. Blackhall, Judith Cave, Kevin G. Blyth, Arjun Nair, Asia Ahmed, Magali N. Taylor, Alexander James Procter, Mary Falzon, David Lawrence, Neal Navani, Ricky M. Thakrar, Sam M. Janes, Dionysis Papadatos-Pastos, Martin D. Forster, Siow Ming Lee, Tanya Ahmad, Sergio A. Quezada, Karl S. Peggs, Peter Van Loo, Caroline Dive, Allan Hackshaw, Nicolai J. Birkbak, Simone Zaccaria, Mariam Jamal-Hanjani (), Nicholas McGranahan () and Charles Swanton ()
Additional contact information
Maise Al Bakir: University College London Cancer Institute
Ariana Huebner: University College London Cancer Institute
Carlos Martínez-Ruiz: University College London Cancer Institute
Kristiana Grigoriadis: University College London Cancer Institute
Thomas B. K. Watkins: The Francis Crick Institute
Oriol Pich: The Francis Crick Institute
David A. Moore: University College London Cancer Institute
Selvaraju Veeriah: University College London Cancer Institute
Sophia Ward: University College London Cancer Institute
Joanne Laycock: University College London Cancer Institute
Diana Johnson: University College London Cancer Institute
Andrew Rowan: The Francis Crick Institute
Maryam Razaq: University College London Cancer Institute
Mita Akther: University College London Cancer Institute
Cristina Naceur-Lombardelli: University College London Cancer Institute
Paulina Prymas: University College London Cancer Institute
Antonia Toncheva: University College London Cancer Institute
Sonya Hessey: University College London Cancer Institute
Michelle Dietzen: University College London Cancer Institute
Emma Colliver: The Francis Crick Institute
Alexander M. Frankell: University College London Cancer Institute
Abigail Bunkum: University College London Cancer Institute
Emilia L. Lim: University College London Cancer Institute
Takahiro Karasaki: University College London Cancer Institute
Christopher Abbosh: University College London Cancer Institute
Crispin T. Hiley: University College London Cancer Institute
Mark S. Hill: The Francis Crick Institute
Daniel E. Cook: The Francis Crick Institute
Gareth A. Wilson: The Francis Crick Institute
Roberto Salgado: ZAS Hospitals
Emma Nye: The Francis Crick Institute
Richard Kevin Stone: The Francis Crick Institute
Dean A. Fennell: University of Leicester
Gillian Price: Aberdeen Royal Infirmary NHS Grampian
Keith M. Kerr: University of Aberdeen
Babu Naidu: University of Birmingham
Gary Middleton: University Hospital Birmingham NHS Foundation Trust
Yvonne Summers: The University of Manchester and The Christie NHS Foundation Trust
Colin R. Lindsay: The University of Manchester and The Christie NHS Foundation Trust
Fiona H. Blackhall: The University of Manchester and The Christie NHS Foundation Trust
Judith Cave: University Hospital Southampton NHS Foundation Trust
Kevin G. Blyth: University of Glasgow
Arjun Nair: University College London Hospitals
Asia Ahmed: University College London Hospitals
Magali N. Taylor: University College London Hospitals
Alexander James Procter: University College London Hospitals
Mary Falzon: University College London Hospitals
David Lawrence: University College London Hospital NHS Trust
Neal Navani: University College London
Ricky M. Thakrar: University College London
Sam M. Janes: University College London
Dionysis Papadatos-Pastos: University College London Hospitals
Martin D. Forster: University College London Cancer Institute
Siow Ming Lee: University College London Cancer Institute
Tanya Ahmad: University College London Hospitals
Sergio A. Quezada: University College London Cancer Institute
Karl S. Peggs: University College London Hospitals
Peter Van Loo: The Francis Crick Institute
Caroline Dive: University of Manchester
Allan Hackshaw: Cancer Research UK & UCL Cancer Trials Centre
Nicolai J. Birkbak: University College London Cancer Institute
Simone Zaccaria: University College London Cancer Institute
Mariam Jamal-Hanjani: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute
Charles Swanton: University College London Cancer Institute

Nature, 2023, vol. 616, issue 7957, 534-542

Abstract: Abstract Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Date: 2023
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DOI: 10.1038/s41586-023-05729-x

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