{"entity":{"id":"paper-tracerx-100-nejm-2017","kind":"paper","name":"TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse","aka":[],"tldr":"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.","summary":"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.\n\nIntratumour 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.\n\nA companion paper (Abbosh, Nature 2017) showed phylogenetic ctDNA tracking could detect relapse a median 70 days before imaging.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1056/NEJMoa1616288"},{"label":"Phylogenetic ctDNA analysis (Abbosh 2017)","url":"https://doi.org/10.1038/nature22364"},{"label":"ClinicalTrials.gov NCT01888601","url":"https://clinicaltrials.gov/study/NCT01888601"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28445112/"}],"tags":[],"related":["paper-gerlinger-intratumour-heterogeneity-nejm-2012","paper-tracerx-evolution-nature-2023","whole-genome-doubling","idea-bio1-clonal-neoantigen-vaccines","paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017","paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011"],"cancers":["nsclc","lung-cancer","resectable-nsclc"],"sections":["diagnostics"],"technologies":["wes-wgs","liquid-biopsy","mrd-testing","ngs"],"targets":["egfr","kras","tp53","met","braf"],"drugs":[],"companies":[],"institutions":["francis-crick","cruk"],"pathways":["clonal-evolution","chromosomal-instability"],"terms":["ctdna","mrd","neoantigen","driver-mutation","biopsy","clonal-evolution"],"trials":[],"people":["charles-swanton"],"bottlenecks":["b-tumor-heterogeneity","b-dormancy-mrd","b-resistance","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2017,"doi":"10.1056/NEJMoa1616288","pmid":"28445112","authors":"Jamal-Hanjani M, Wilson GA, McGranahan N, et al. (TRACERx Consortium)","paperType":"translational","findings":["327 regions from 100 tumours; median 30% of mutations subclonal, 48% of tumours with subclonal drivers","Elevated copy-number intratumour heterogeneity associated with recurrence or death: HR 4.9 (95% CI 1.8-13.1)","EGFR, MET, BRAF and TP53 mutations almost always clonal; PIK3CA, NF1 and chromatin-modifier mutations often subclonal","Whole-genome doubling occurred in most tumours and preceded much of the copy-number diversification","Companion ctDNA paper: relapse detected a median 70 days before CT in tracked patients"],"whatItMeans":"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.","caveats":["Early-stage, surgically resected tumours only; the interim cohort of 100 was later expanded to 421","Exome sequencing does not capture non-coding or structural events fully","The prognostic value of copy-number heterogeneity needed validation in the full cohort and other cancers","Clinical utility of clonal-neoantigen targeting remained hypothetical at the time"],"changedPractice":false,"participants":100},"route":"/key-papers/paper-tracerx-100-nejm-2017/","neighbours":{"paper":[{"id":"paper-zhang-lung-cancer-never-smokers-nat-genet-2021","kind":"paper","name":"Genomic and evolutionary classification of lung cancer in never smokers","route":"/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/"},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/"},{"id":"paper-gerlinger-intratumour-heterogeneity-nejm-2012","kind":"paper","name":"Gerlinger: a single biopsy misses most of the mutations in a kidney tumour","route":"/key-papers/paper-gerlinger-intratumour-heterogeneity-nejm-2012/"},{"id":"paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023","kind":"paper","name":"Lung adenocarcinoma promotion by air pollutants","route":"/key-papers/paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023/"},{"id":"paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017","kind":"paper","name":"Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution","route":"/key-papers/paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017/"},{"id":"paper-tracerx-evolution-nature-2023","kind":"paper","name":"TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse","route":"/key-papers/paper-tracerx-evolution-nature-2023/"}],"term":[{"id":"biopsy","kind":"term","name":"Biopsy","route":"/terms/biopsy/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"whole-genome-doubling","kind":"term","name":"Whole-genome doubling (WGD)","route":"/terms/whole-genome-doubling/"}],"idea":[{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/"},{"id":"idea-bio1-clonal-neoantigen-vaccines","kind":"idea","name":"Vaccines aimed only at mutations shared by every tumour cell","route":"/ideas/idea-bio1-clonal-neoantigen-vaccines/"}],"cancer":[{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"resectable-nsclc","kind":"cancer","name":"Resectable stage I to III non-small-cell lung cancer","route":"/cancers/resectable-nsclc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"met","kind":"target","name":"MET","route":"/targets/met/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"cruk","kind":"institution","name":"Cancer Research UK","route":"/institutions/cruk/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"}],"person":[{"id":"charles-swanton","kind":"person","name":"Charles Swanton","route":"/people/charles-swanton/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/lung-cancer-evidence-roadmap/"}]}}