Clonal evolution & minimal residual disease
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.
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.
In one picture
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.
Diagram
top- 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
top- Leading programmes: Swanton (Crick, TRACERx); Gatenby and Brown (Moffitt, adaptive therapy); Getz (Broad) on clonal reconstruction; Landau (Weill Cornell) on single-cell evolution.
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 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.
Carrying a cancer mutation is normal; most mutant clones never become cancer. This means blood or tissue tests that look for driver mutations alone will produce false positives, and that the question of what tips a mutant clone into cancer (tissue environment, further hits, immune surveillance) is as important as the mutation itself.
Many older people carry blood clones one or two steps from leukaemia, and those clones also drive heart disease through inflammation. CHIP is why blood-based cancer tests must filter out mutations from blood cells, and it opens a route to preventing both leukaemia and cardiovascular events in carriers.
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.