The evolution of non-small cell lung cancer metastases in TRACERx
Authors: Al Bakir Maise , Huebner Ariana , Martínez-Ruiz Carlos , Grigoriadis Kristiana , Watkins Thomas B. K. , Pich Oriol , Moore David A. , Veeriah Selvaraju , Ward Sophia , Laycock Joanne , Johnson Diana , Rowan Andrew , Razaq Maryam , Akther Mita , Naceur-Lombardelli Cristina , Prymas Paulina , Toncheva Antonia , Hessey Sonya , Dietzen Michelle , Colliver Emma , Frankell Alexander M. , Bunkum Abigail , Lim Emilia L. , Karasaki Takahiro , Abbosh Christopher , Hiley Crispin T. , Hill Mark S. , Cook Daniel E. , Wilson Gareth A. , Salgado Roberto , Nye Emma , Stone Richard Kevin , Fennell Dean A. , Price Gillian , Kerr Keith M. , Naidu Babu , Middleton Gary , Summers Yvonne , Lindsay Colin R. , Blackhall Fiona H. , Cave Judith , Blyth Kevin G. , Nair Arjun , Ahmed Asia , Taylor Magali N. , Procter Alexander James , Falzon Mary , Lawrence David , Navani Neal , Thakrar Ricky M. , Janes Sam M. , Papadatos-Pastos Dionysis , Forster Martin D. , Lee Siow Ming , Ahmad Tanya , Quezada Sergio A. , Peggs Karl S. , Van Loo Peter , Dive Caroline , Hackshaw Allan , Birkbak Nicolai J. , Zaccaria Simone ,   TRACERx Consortium, Lester Jason F. , Bajaj Amrita , Nakas Apostolos , Sodha-Ramdeen Azmina , Ang Keng , Tufail Mohamad , Chowdhry Mohammed Fiyaz , Scotland Molly , Boyles Rebecca , Rathinam Sridhar , Wilson Claire , Marrone Domenic , Dulloo Sean , Matharu Gurdeep , Shaw Jacqui A. , Riley Joan , Primrose Lindsay , Boleti Ekaterini , Cheyne Heather , Khalil Mohammed , Richardson Shirley , Cruickshank Tracey , Benafif Sarah , Gilbert Kayleigh , Patel Akshay J. , Osman Aya , Lacson Christer , Langman Gerald , Shackleford Helen , Djearaman Madava , Kadiri Salma , Leek Angela , Hodgkinson Jack Davies , Totten Nicola , Montero Angeles , Smith Elaine , Fontaine Eustace , Granato Felice , Doran Helen , Novasio Juliette , Rammohan Kendadai , Joseph Leena , Bishop Paul , Shah Rajesh , Moss Stuart , Joshi Vijay , Crosbie Philip , Gomes Fabio , Brown Kate , Carter Mathew , Chaturvedi Anshuman , Priest Lynsey , Oliveira Pedro , Krebs Matthew G. , Clipson Alexandra , Tugwood Jonathan , Kerr Alastair , Rothwell Dominic G. , Kilgour Elaine , Aerts Hugo J. W. L. , Schwarz Roland F. , Kaufmann Tom L. , Rosenthal Rachel , Szallasi Zoltan , Kisistok Judit , Sokac Mateo , Diossy Miklos , Demeulemeester Jonas , Stewart Aengus , Magness Alastair , Karamani Angeliki , Chain Benny , Campbell Brittany B. , Castignani Carla , Bailey Chris , Puttick Clare , Weeden Clare E. , Lee Claudia , Richard Corentin , Pearce David R. , Karagianni Despoina , Biswas Dhruva , Levi Dina , Hoxha Elena , Larose Cadieux Elizabeth , Grönroos Eva , Gálvez-Cancino Felip , Athanasopoulou Foteini , Gimeno-Valiente Francisco , Kassiotis George , Stavrou Georgia , Mastrokalos Gerasimos , Zhai Haoran , Lowe Helen L. , Matos Ignacio , Goldman Jacki , Reading James L. , Black James R. M. , Herrero Javier , Rane Jayant K. , Nicod Jerome , Lam Jie Min , Hartley John A. , Enfield Katey S. S. , Selvaraju Kayalvizhi , Thol Kerstin , Litchfield Kevin , Ng Kevin W. , Chen Kezhong , Dijkstra Krijn , Thakkar Krupa , Ensell Leah , Shah Mansi , Vasquez Marcos , Litovchenko Maria , Werner Sunderland Mariana , Leung Michelle , Escudero Mickael , Angelova Mihaela , Tanić Miljana , Sivakumar Monica , Kanu Nnennaya , Chervova Olga , Lucas Olivia , Al-Sawaf Othman , Hobson Philip , Pawlik Piotr , Bentham Robert , Hynds Robert E. , Vendramin Roberto , Saghafinia Sadegh , López Saioa , Gamble Samuel , Ung Seng Kuong Anakin , Vanloo Sharon , Boeing Stefan , Beck Stephan , Bola Supreet Kaur , Denner Tamara , Marafioti Teresa , Mourikis Thanos P. , Spanswick Victoria , Barbè Vittorio , Lu Wei-Ting , Hill William , Liu Wing Kin , Wu Yin , Naito Yutaka , Ramsden Zoe , Veiga Catarina , Royle Gary , Collins-Fekete Charles-Antoine , Fraioli Francesco , Ashford Paul , Clark Tristan , Borg Elaine , Wilson James , Patrini Davide , Martinoni Hoogenboom Emilie , Monk Fleur , Holding James W. , Choudhary Junaid , Bhakhri Kunal , Scarci Marco , Hayward Martin , Panagiotopoulos Nikolaos , Gorman Pat , Khiroya Reena , Stephens Robert C. M. , Wong Yien Ning Sophia , Bandula Steve , Sharp Abigail , Smith Sean , Gower Nicole , Dhanda Harjot Kaur , Chan Kitty , Pilotti Camilla , Leslie Rachel , Grapa Anca , Zhang Hanyun , AbdulJabbar Khalid , Pan Xiaoxi , Yuan Yinyin , Chuter David , MacKenzie Mairead , Chee Serena , Alzetani Aiman , Scarlett Lydia , Richards Jennifer , Ingram Papawadee , Austin Silvia , Lim Eric , De Sousa Paulo , Jordan Simon , Rice Alexandra , Raubenheimer Hilgardt , Bhayani Harshil , Ambrose Lyn , Devaraj Anand , Chavan Hema , Begum Sofina , Buderi Silviu I. , Kaniu Daniel , Malima Mpho , Booth Sarah , Nicholson Andrew G. , Fernandes Nadia , Shah Pratibha , Proli Chiara , Hewish Madeleine , Danson Sarah , Shackcloth Michael J. , Robinson Lily , Russell Peter , Dick Craig , Le Quesne John , Kirk Alan , Asif Mo , Bilancia Rocco , Kostoulas Nikos , Thomas Mathew , Jamal-Hanjani Mariam , McGranahan Nicholas , Swanton Charles 
Published: April 2023

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.