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

Maise Al Bakir, Ariana Huebner, Carlos Martinez-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 ColliverAlexander 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, Hugo J. W. L. Aerts, TRACERx Consortium, Mariam Jamal-Hanjani*, Nicholas McGranahan*, Charles Swanton*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Metastatic disease is responsible for the majority of cancer-related deaths(1). 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.
Original languageEnglish
Pages (from-to)534-542
Number of pages34
Issue number7957
Early online date1 Apr 2023
Publication statusPublished - 20 Apr 2023




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