{"entity":{"id":"clonal-evolution-theory","kind":"term","name":"Clonal evolution and the ecological view of cancer","aka":["clonal evolution theory","evolutionary theory of cancer","cancer as an evolutionary process","ecological view of cancer","Darwinian model of cancer","branched evolution"],"tldr":"A tumour is a population of cells that mutate, compete and are selected, exactly as species are, and treatment is one more selective pressure. Peter Nowell proposed this in 1976; it explains why tumours are mixtures of clones, why resistance to almost any single drug appears, and why some researchers now try to steer a tumour's evolution rather than eradicate it.","summary":"The claim. Cancer proceeds by Darwinian evolution within the body: heritable variation (mutations, epigenetic states, chromosome changes) arises in a founding clone, natural selection in the tissue favours variants that grow or survive better, and the tumour diversifies into subclones. The ecological extension (Merlo, Maley, Gatenby) adds that cells compete for space, oxygen and nutrients, cooperate through shared growth factors and face predators in the immune system, so a tumour is an ecosystem and therapy is a perturbation of it.\n\nWho and when. Nowell's 1976 Science paper The clonal evolution of tumor cell populations stated the theory and predicted that each patient's tumour would be genetically unique and that therapy would select resistant variants. Cairns (1975) argued that tissue architecture limits somatic evolution. Merlo, Pepper, Reid and Maley (2006) set out cancer as an evolutionary and ecological process; Greaves and Maley reviewed the evidence in 2012; Gerlinger and Swanton's 2012 multi-region sequencing of kidney cancer showed branched evolution directly; Gatenby proposed adaptive therapy in 2009 and Zhang and colleagues reported a pilot in prostate cancer in 2017; Sottoriva and Graham proposed the Big Bang model of colorectal tumour growth in 2015.\n\nEvidence for. Multi-region and single-cell sequencing show every tumour as a tree of related clones with a truncal set of early mutations and branches that differ between regions and metastases. Resistance arises by selection of pre-existing or newly mutated clones (EGFR T790M and C797S in lung cancer, KRAS clones under EGFR antibodies in colorectal cancer, BCR::ABL1 T315I in chronic myeloid leukaemia), and circulating tumour DNA tracks their rise and fall in real time. Intratumour heterogeneity predicts worse outcome. Mel Greaves' studies of childhood leukaemia in twins showed the founding clone can form in the womb years before diagnosis.\n\nEvidence against and limits. Some tumours evolve neutrally after an early burst rather than by continuous selection (the Big Bang model), and some change by punctuated catastrophe (chromothripsis, whole-genome doubling) rather than gradual accumulation. Evolution is hard to predict for an individual patient, and the theory does not by itself say what starts the process. Randomised evidence that evolution-informed dosing beats standard dosing is still awaited.\n\nPredictions that held or failed. Held: acquired resistance to any single targeted drug is close to inevitable; combinations and sequential monitoring delay it; rechallenge with an EGFR antibody works after resistant clones recede (CHRONOS). Failed: the Goldie-Coldman prediction that alternating non-cross-resistant regimens would improve outcomes was not borne out in trials; efforts to model a tumour's trajectory precisely enough to time therapy remain experimental.\n\nTherapies that came from it. Combination therapy as a principle, minimal residual disease monitoring, liquid biopsy surveillance for resistance mutations, adaptive and intermittent dosing (adaptive therapy in prostate cancer), evolutionary herding and collateral sensitivity, and the mathematical oncology programme that models these dynamics. It is the theory the driver and passenger model feeds into, the ageing tissue view builds on (aged tissue changes what is selected), and the immunoediting theory applies to the immune system as predator.\n\nStatus: established. Tumours evolve, and the clinic already acts on it through monitoring and combinations; the ecological programme of steering evolution rather than eradicating the tumour is partly confirmed and awaits randomised trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Somatic_evolution_in_cancer","links":[{"label":"Nowell, The clonal evolution of tumor cell populations (Science 1976)","url":"https://doi.org/10.1126/science.959840"},{"label":"Merlo, Pepper, Reid and Maley, Cancer as an evolutionary and ecological process (Nature Reviews Cancer 2006)","url":"https://doi.org/10.1038/nrc2013"},{"label":"Greaves and Maley, Clonal evolution in cancer (Nature 2012)","url":"https://doi.org/10.1038/nature10762"},{"label":"Gerlinger et al., Intratumor heterogeneity and branched evolution revealed by multiregion sequencing (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"},{"label":"Gatenby et al., Adaptive therapy (Cancer Research 2009)","url":"https://doi.org/10.1158/0008-5472.CAN-08-3658"},{"label":"Zhang et al., Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer (Nature Communications 2017)","url":"https://doi.org/10.1038/s41467-017-01968-5"},{"label":"Sottoriva et al., A Big Bang model of human colorectal tumor growth (Nature Genetics 2015)","url":"https://doi.org/10.1038/ng.3214"}],"tags":["theory"],"related":["theories-of-cancer","somatic-mutation-theory","driver-passenger-model","ageing-tissue-field-theory","immune-surveillance-immunoediting","aneuploidy-theory-of-cancer","cancer-stem-cell-theory","clonal-evolution","clonal-evolution-models","adaptive-therapy-dynamics","evolutionary-game-theory-cancer","mathematical-oncology","drug-tolerant-persisters","field-cancerisation","resistance","mrd","ctdna"],"cancers":["cml","nsclc","colorectal","prostate"],"sections":[],"technologies":["mrd-testing","liquid-biopsy","wes-wgs","adaptive-therapy-dynamics","clonal-evolution-models","evolutionary-game-theory-cancer"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["clonal-evolution","drug-tolerant-persisters","field-cancerisation","resistance-routes-map"],"terms":[],"trials":[],"people":["mel-greaves","robert-gatenby","charles-swanton"],"bottlenecks":[],"keyPapers":["paper-gerlinger-intratumour-heterogeneity-nejm-2012"],"journals":[],"dependsOn":[],"notes":[],"category":"Cancer biology"},"route":"/terms/clonal-evolution-theory/","neighbours":{"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"id":"field-cancerisation","kind":"pathway","name":"Field cancerisation","route":"/pathways/field-cancerisation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"}],"term":[{"id":"ageing-tissue-field-theory","kind":"term","name":"Ageing tissue and clonal fields: cancer as a disease of old tissue","route":"/terms/ageing-tissue-field-theory/"},{"id":"aneuploidy-theory-of-cancer","kind":"term","name":"Aneuploidy and chromosomal instability as the cause of cancer","route":"/terms/aneuploidy-theory-of-cancer/"},{"id":"atavistic-theory-of-cancer","kind":"term","name":"Atavistic theory: cancer as a reversion to an ancient programme","route":"/terms/atavistic-theory-of-cancer/"},{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"driver-passenger-model","kind":"term","name":"Driver and passenger mutations: the refined somatic mutation theory","route":"/terms/driver-passenger-model/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"hallmarks-synthesis","kind":"term","name":"Hallmarks of cancer as a synthesis of the theories","route":"/terms/hallmarks-synthesis/"},{"id":"immune-surveillance-immunoediting","kind":"term","name":"Immune surveillance and cancer immunoediting","route":"/terms/immune-surveillance-immunoediting/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"seed-and-soil-hypothesis","kind":"term","name":"Seed and soil hypothesis of metastasis (Paget)","route":"/terms/seed-and-soil-hypothesis/"},{"id":"somatic-mutation-theory","kind":"term","name":"Somatic mutation theory of cancer","route":"/terms/somatic-mutation-theory/"}],"technology":[{"id":"adaptive-therapy-dynamics","kind":"technology","name":"Adaptive therapy (evolution-based dosing)","route":"/technologies/adaptive-therapy-dynamics/"},{"id":"clonal-evolution-models","kind":"technology","name":"Clonal evolution and branching models","route":"/technologies/clonal-evolution-models/"},{"id":"evolutionary-game-theory-cancer","kind":"technology","name":"Evolutionary game theory in cancer","route":"/technologies/evolutionary-game-theory-cancer/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mathematical-oncology","kind":"technology","name":"Mathematical models of cancer (mathematical oncology)","route":"/technologies/mathematical-oncology/"},{"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/"}],"cancer":[{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"person":[{"id":"charles-swanton","kind":"person","name":"Charles Swanton","route":"/people/charles-swanton/"},{"id":"mel-greaves","kind":"person","name":"Mel Greaves","route":"/people/mel-greaves/"},{"id":"robert-gatenby","kind":"person","name":"Robert A. 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