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Multi-region sequencing of 327 regions from the first 100 TRACERx lung cancers showed that most driver mutations are early and shared while copy-number chaos continues to evolve, and that tumours with high copy-number heterogeneity were nearly five times more likely to relapse or kill the patient.
TRACERx (TRAcking Cancer Evolution through therapy) is a Cancer Research UK prospective study following patients with resected stage I-IIIA non-small-cell lung cancer from surgery to relapse or death. This first report analysed 327 tumour regions from 100 patients with whole-exome sequencing.
Intratumour heterogeneity was pervasive: a median of 30% of mutations were subclonal, and 48% of tumours had subclonal driver alterations. Driver mutations in EGFR, MET, BRAF and TP53 were almost always clonal (early), whereas alterations in PIK3CA, NF1 and chromatin modifiers were often late. Ongoing chromosomal instability (subclonal copy-number alterations) rather than mutational heterogeneity predicted recurrence-free survival: patients whose tumours had elevated copy-number heterogeneity had a hazard ratio of 4.9 for recurrence or death.
A companion paper (Abbosh, Nature 2017) showed phylogenetic ctDNA tracking could detect relapse a median 70 days before imaging.
Lung cancers keep evolving after they form, and it is ongoing chromosomal instability rather than the number of mutations that best predicts who will relapse. This gives a rationale for targeting the earliest (clonal) drivers and neoantigens and for tracking evolution in blood after surgery.
It reframes air quality as cancer policy rather than respiratory policy, and it explains the shape of lung cancer in never-smokers: the mutations are common and mostly silent, and what differs is whether something inflames the tissue enough to let one of them grow.
Relapse after surgery is driven by particular subclones that can be identified in the primary tumour and tracked in blood, which argues for evolution-aware adjuvant strategies. The pollution finding reframes carcinogenesis: some agents promote already-mutant cells rather than causing mutations.
Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
The foundation of minimal residual disease testing in lung cancer: a blood test that says a patient will relapse months before a scan does, and says which part of the tumour is doing it. Whether acting on that signal changes outcome is what the ctDNA-guided trials are for.
A single biopsy is an incomplete picture of a patient's cancer. Truncal mutations shared by all cells (in kidney cancer, VHL) are the most reliable drug targets, whereas mutations in only some branches predict resistance. This is why liquid biopsy and multi-region sampling matter.
The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became.
Shares Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch.
Shares Biopsy, MET, Next-generation sequencing (NGS), BRAF.
Shares Lung adenocarcinoma promotion by air pollutants, Genomic and evolutionary classification of lung cancer in never smokers, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Whole-exome & whole-genome sequencing.
Shares Biopsy, MET, Next-generation sequencing (NGS), BRAF.
Shares Gerlinger: a single biopsy misses most of the mutations in a kidney tumour, Tumour heterogeneity and clonal evolution, Acquired resistance to every therapy, Circulating tumour DNA (ctDNA).
Shares Lung adenocarcinoma promotion by air pollutants, TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse, The Francis Crick Institute, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch.
Shares Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Driver mutation, MET.
Shares Whole-genome doubling (WGD), Chromosomal instability & aneuploidy, Clonal evolution & minimal residual disease, Whole-exome & whole-genome sequencing.