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 Stone, Dean A. Fennell, Gillian Price, Keith M. Kerr, Babu Naidu, Gary Middleton, Yvonne Summers, Colin R. Lindsay, Fiona 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 Förster, Siow Ming Lee, Tanya Ahmad, Sergio A. Quezada, Karl S. Peggs, Peter Van Loo, Caroline Dive, Allan Hackshaw, Nicolai J. Birkbak, Simone Zaccaria, J.F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Keng Ang, Mohamad Tufail, Mohammed Fiyaz Chowdhry, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Gurdeep Matharu, Jacqui Shaw, Joan Riley, Lindsay Primrose, Ekaterini Boleti, Heather Cheyne, Mohammed S. Khalil, Shirley Richardson, Tracey Cruickshank, Sarah Benafif, Kayleigh Gilbert, Akshay J. Patel, Aya Osman, Christer Lacson, Gerald Langman, Helen Shackleford, Madava Djearaman, Salma Kadiri, Angela Leek, Jack Davies Hodgkinson, Nicola Totten, Ángeles Montero, Elaine Smith, Eustace Fontaine, Felice Granato
Abstract
. 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.