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TRACERx sequenced several regions of 100 lung tumours instead of one. The driver mutations were usually everywhere in the tumour, but three quarters had later mutations present in only part of it, and the messier the tumour, the worse the outcome.
The TRACERx consortium, reported by Jamal-Hanjani, Wilson, McGranahan and colleagues with Swanton as senior author, performed multiregion whole-exome sequencing on 100 early-stage non-small-cell lung cancers resected before systemic therapy, analysing 327 tumour regions.
It is the study that made intratumour heterogeneity a measurable prognostic variable rather than a caveat. The practical consequence is that a single biopsy describes a sample of a tumour, not the tumour, and that chromosomal instability rather than mutation count is what tracks with recurrence.
Why targeting a clonal driver works and targeting a subclonal one usually does not, and why a single-site biopsy can mislead. Chromosomal instability is now a candidate prognostic marker in its own right.
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.
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.
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, Next-generation sequencing (NGS) and the tag lung-evidence.
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 and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), MET, 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 and the tag lung-evidence.
Shares Genomic and evolutionary classification of lung cancer in never smokers, Lung adenocarcinoma promotion by air pollutants, 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 and the tag lung-evidence.
Shares 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, Acquired resistance to every therapy, Biomarkers are not validated or standardised and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), 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, Biomarkers are not validated or standardised and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), 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, Biomarkers are not validated or standardised and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), MET, 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 and the tag lung-evidence.