Nature. 2017 Apr 26. doi: 10.1038/nature22364. [Epub ahead of print]
Abbosh C1,
Birkbak NJ1,2,
Wilson GA1,2,
Jamal-Hanjani M1,
Constantin T3,
Salari R3,
Quesne JL4,
Moore DA4,
Veeriah S1,
Rosenthal R1,
Marafioti T1,5,
Kirkizlar E3,
Watkins TBK1,2,
McGranahan N1,2,
Ward S1,2,6,
Martinson L4,
Riley J4,
Fraioli F7,
Bakir MA2,
GrĂ–nroos E2,
Zambrana F1,
Endozo R7,
Bi WL8,9,
Fennessy FM8,9,
Sponer N3,
Johnson D1,
Laycock J1,
Shafi S1,
Czyzewska-Khan J1,
Rowan A2,
Chambers T2,6,
Matthews N6,10,
Turajlic S2,11,
Hiley C1,2,
Lee SM12,1,
Forster MD1,12,
Ahmad T12,
Falzon M5,
Borg E5,
Lawrence D13,
Hayward M13,
Kolvekar S13,
Panagiotopoulos N13,
Janes SM1,14,15,
Thakrar R14,
Ahmed A16,
Blackhall F17,18,
Summers Y18,
Hafez D3,
Naik A3,
Ganguly A3,
Kareht S3,
Shah R19,
Joseph L20,
Quinn AM20,
Crosbie P21,
Naidu B22,
Middleton G23,
Langman G24,
Trotter S24,
Nicolson M25,
Remmen H26,
Kerr K27,
Chetty M28,
Gomersall L29,
Fennell DA4,
Nakas A30,
Rathinam S30,
Anand G31,
Khan S32,33,
Russell P34,
Ezhil V35,
Ismail B36,
Irvin-Sellers M37,
Prakash V38,
Lester JF39,
Kornaszewska M40,
Attanoos R41,
Adams H42,
Davies H43,
Oukrif D1,
Akarca AU1,
Hartley JA44,
Lowe HL44,
Lock S45,
Iles N46,
Bell H46,
Ngai Y46,
Elgar G2,6,
Szallasi Z47,48,49,
Schwarz RF50,
Herrero J51,
Stewart A52,
Quezada SA53,
Van Loo P54,55,
Dive C1,56,
Lin CJ3,
Rabinowitz M3,
Aerts HJ8,9,57,
Hackshaw A46,
Shaw JA4,
Zimmermann BG3;
TRACERx consortium;
PEACE consortium,
Swanton C1,2.
Abstract
The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early–stage lung cancer is not established. Here we conduct a tumour-specific phylogenetic approach to ctDNA profiling in the first 100 TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lungcancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.