# Clonal evolution & minimal residual disease

Source: https://onco.cc/pathways/clonal-evolution/  
OnCo record `clonal-evolution` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A tumour is a population that evolves by natural selection. Treatment kills the sensitive cells and selects the rest, which is why resistance is the rule; measuring the surviving population (MRD) and adapting therapy is the counter-strategy.

## Summary

Truncal mutations are shared by all cells; branched subclones carry private alterations (TRACERx, PCAWG). Therapy imposes selection: pre-existing resistant clones (EGFR T790M, ESR1) expand, or drug-tolerant persisters acquire mutations later. Neutral and punctuated evolution, whole-genome doubling, and CIN modulate the tempo. ctDNA lets clonal dynamics be followed in real time; MRD detection after curative therapy identifies who will relapse. Adaptive therapy (dose modulation to maintain sensitive competitors, Moffitt prostate pilot) and combination strategies aim to steer rather than merely suppress evolution.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- Analogy: Clonal evolution is like weeding a field with one herbicide year after year: the field fills with the one weed that shrugs it off. Rotating herbicides and leaving some susceptible weeds to crowd out the resistant ones is the evolutionary alternative.
- Interventions: ctDNA MRD to escalate or de-escalate (IMvigor011, DYNAMIC); Upfront combinations to pre-empt resistant clones (osimertinib + chemotherapy, BRAF + MEK); Adaptive therapy trials (Moffitt); Serial liquid biopsy to switch therapy at molecular progression (SERENA-6)

## Notes

- Leading programmes: Swanton (Crick, TRACERx); Gatenby and Brown (Moffitt, adaptive therapy); Getz (Broad) on clonal reconstruction; Landau (Weill Cornell) on single-cell evolution.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Somatic_evolution_in_cancer
- Jamal-Hanjani et al., Tracking the evolution of non-small-cell lung cancer (NEJM 2017): https://doi.org/10.1056/NEJMoa1616288
- Zhang et al., Integrating evolutionary dynamics into treatment of mCRPC (Nature Communications 2017): https://doi.org/10.1038/s41467-017-01968-5

## Connected records

- pathways: [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Clonal haematopoiesis (CHIP)](https://onco.cc/pathways/clonal-haematopoiesis/), [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [Field cancerisation](https://onco.cc/pathways/field-cancerisation/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/), [The metastatic cascade](https://onco.cc/pathways/metastatic-cascade/), [Theories of cancer: how the ideas connect](https://onco.cc/pathways/theories-of-cancer/), [Tumour dormancy](https://onco.cc/pathways/tumor-dormancy/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Clonal evolution and the ecological view of cancer](https://onco.cc/terms/clonal-evolution-theory/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Intra-tumour heterogeneity](https://onco.cc/terms/intra-tumour-heterogeneity/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Mutational signature](https://onco.cc/terms/mutational-signature/), [Rechallenge and retreatment](https://onco.cc/terms/rechallenge/), [Transformation: when a slow lymphoma turns into a fast one](https://onco.cc/terms/lymphoma-bio-transformation/), [Tumour evolution (somatic evolution)](https://onco.cc/terms/tumour-evolution/), [Variant allele frequency (VAF)](https://onco.cc/terms/vaf/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [Moffitt Cancer Center](https://onco.cc/institutions/moffitt/), [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/)
- trials: [DYNAMIC](https://onco.cc/trials/dynamic/), [IMvigor011](https://onco.cc/trials/imvigor011/)
- key papers: [A genetic model for colorectal tumorigenesis](https://onco.cc/key-papers/paper-fearon-cell/), [A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns](https://onco.cc/key-papers/paper-notta-punctuated-evolution-pancreatic-nature-2016/), [A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-hayashi-squamous-basal-like-pancreatic-nat-cancer-2020/), [Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain](https://onco.cc/key-papers/paper-pao-egfr-t790m-acquired-resistance-plos-med-2005/), [Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib](https://onco.cc/key-papers/paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018/), [Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas](https://onco.cc/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/), [Concordance of circulating tumour DNA and matched metastatic tissue biopsy in prostate cancer](https://onco.cc/key-papers/paper-wyatt-ctdna-tissue-concordance-mcrpc-jnci-2017/), [Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes](https://onco.cc/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/), [Distant metastasis occurs late during the genetic evolution of pancreatic cancer](https://onco.cc/key-papers/paper-yachida-metastasis-late-genetic-evolution-pancreatic-nature-2010/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer](https://onco.cc/key-papers/paper-misale-kras-acquired-resistance-anti-egfr-colorectal-nature-2012/), [Genomic and evolutionary classification of lung cancer in never smokers](https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/), [Genomic characterization of malignant progression in neoplastic pancreatic cysts](https://onco.cc/key-papers/paper-noe-cyst-malignant-progression-genomics-nat-commun-2020/), [Genomic characterization of metastatic breast cancers](https://onco.cc/key-papers/paper-bertucci-metastatic-breast-genomics-nature-2019/), [Genomics of lethal prostate cancer at diagnosis and castration resistance](https://onco.cc/key-papers/paper-mateo-genomics-lethal-prostate-diagnosis-castration-resistance-jci-2020/), [Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors](https://onco.cc/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/), [Gerlinger: a single biopsy misses most of the mutations in a kidney tumour](https://onco.cc/key-papers/paper-gerlinger-intratumour-heterogeneity-nejm-2012/), [Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories](https://onco.cc/key-papers/paper-taylor-germline-brca2-evolutionary-trajectories-nat-commun-2017/), [Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer](https://onco.cc/key-papers/paper-zhang-nat-commun/), [IPMNs with co-occurring invasive cancers: neighbours but not always relatives](https://onco.cc/key-papers/paper-felsenstein-ipmn-cooccurring-cancer-relatedness-gut-2018/), [Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70](https://onco.cc/key-papers/paper-jaiswal-chip-nejm-2014/), [Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer](https://onco.cc/key-papers/paper-makohon-moore-metastases-driver-homogeneity-nat-genet-2017/), [Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones](https://onco.cc/key-papers/paper-martincorena-somatic-mutations-normal-skin-science-2015/), [Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer](https://onco.cc/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/), [Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features](https://onco.cc/key-papers/paper-omori-ipmn-progression-pathways-gastroenterology-2019/), [Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution](https://onco.cc/key-papers/paper-abbosh-phylogenetic-ctdna-lung-cancer-nature-2017/), [Precancerous neoplastic cells can move through the pancreatic ductal system](https://onco.cc/key-papers/paper-makohon-moore-precursor-cells-ductal-system-nature-2018/), [Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F](https://onco.cc/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/), [Substantial interindividual and limited intraindividual genomic diversity among tumours from men with metastatic prostate cancer](https://onco.cc/key-papers/paper-kumar-interindividual-genomic-diversity-metastatic-prostate-nat-med-2016/), [The clonal and mutational evolution spectrum of primary triple-negative breast cancers](https://onco.cc/key-papers/paper-shah-tnbc-clonal-evolution-nature-2012/), [The landscape of somatic mutation in normal colorectal epithelial cells](https://onco.cc/key-papers/paper-lee-six-somatic-mutation-normal-colorectal-crypts-nature-2019/), [The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers](https://onco.cc/key-papers/paper-diaz-molecular-evolution-egfr-resistance-colorectal-nature-2012/), [The mutational landscape of lethal castration-resistant prostate cancer](https://onco.cc/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/), [TRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapse](https://onco.cc/key-papers/paper-tracerx-evolution-nature-2023/), [TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse](https://onco.cc/key-papers/paper-tracerx-100-nejm-2017/), [Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution](https://onco.cc/key-papers/paper-chan-seng-yue-pancreatic-transcription-phenotypes-nat-genet-2020/)
- targets: [TP53](https://onco.cc/targets/tp53/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Richter transformation of chronic lymphocytic leukaemia](https://onco.cc/cancers/richter-transformation-cll/)
- biomarkers: [ALK kinase-domain resistance mutation (G1202R and the rest)](https://onco.cc/biomarkers/alk-resistance-mutation/), [Circulating tumour DNA fraction (and what a negative plasma result means)](https://onco.cc/biomarkers/ctdna-tumour-fraction/), [Immunoglobulin and T-cell receptor clonality](https://onco.cc/biomarkers/ig-tcr-clonality/)
- ideas: [Attack extrachromosomal DNA, the engine of oncogene amplification](https://onco.cc/ideas/idea-ecdna-targeting/), [Intercept cancer at the field stage](https://onco.cc/ideas/idea-field-interception/), [Kill drug-tolerant persisters through ferroptosis](https://onco.cc/ideas/idea-ferroptosis-persisters/)
- roadmaps: [ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment](https://onco.cc/roadmaps/ctdna-tests/)

---
JSON: https://onco.cc/api/v1/entities/clonal-evolution.json