Evolutionary theory can provide a functional framework for understanding disease and dysfunction. One example of this is therapeutic resistance in cancer, which is fundamentally an evolutionary process. Neoplasms are genetically 
and epigenetically 
diverse populations of billions to trillions of cells. Therapies apply strong selective pressures to these populations, and when they do not cure the patient, they select for resistant populations of neoplastic cells. When the tumor recurs, it now derives from the resistant cells that survived therapy (see ), and so application of the same therapy typically has diminished, if any, effect 
. When tested, the resistant mutations can often be found in the gene targeted by the drug 
and are present in tumor samples taken prior to therapy 
. This shows that therapy did not create the resistance mutations but rather selected the resistant clone from among the standing variation in the cell population at the time of therapy. Every known cancer drug suffers from this problem 
, and it is the primary reason we have not been able to cure cancer. The result is that virtually all cancer deaths are due to therapeutically resistant disease.
Given the magnitude of the problem of therapeutic resistance and fundamentally evolutionary nature of the process, one might expect evolutionary theory and methods to be common in research on therapeutic resistance. However, evolutionary thinking has been strangely absent from research and training in medicine in general 
and evolutionary terms appear rarely in the medical literature on antibiotic resistance 
suggesting that evolutionary approaches to therapeutic resistance in cancer might not be very common.
An evolutionary approach to therapeutic resistance in cancer should involve the use of evolutionary theory and the use of methods that take into account the evolutionary nature of therapeutic resistance. This includes (but is not limited to):
1. Using evolutionary theory
Using evolution to explain how resistance occurs
There are other popular views of resistance that probably play some role in the failure of therapies including: (1) change in phenotype without change in heritable information (such as the [epi]genotype, (2) failure to kill cancer stem cells, (3) too low a dose (toxicity limitations), (4) failure to deliver drug to all the cells (refugia), or (5) between-patient differential sensitivity. However, these other mechanisms of resistance do not lead to the diminishing effectiveness of a drug and so are less clinically problematic than selection for resistant subclones in the tumor. The acquisition of therapeutic resistance is a fundamentally evolutionary process and natural selection is at work during treatment and competitive release (the subsequent increase in population size of the resistance clone because of the removal of competitors), even if other explanations of resistance play some role.
Using evolution as a fundamental theoretical framework
The theory of cancer is a theory of evolution among somatic cells of the body 
. An evolutionary approach to therapeutic resistance depends on the recognition of the population dynamics of somatic cells and selection at that level.
2. Measuring evolution
Examining within-patient/within-tumor heterogeneity
Because evolution is defined as changes in allele frequencies in a population, measuring within-tumor genetic heterogeneity allows for the study of evolutionary dynamics.
Measuring cell fitness
Differential survival and reproduction is necessary for natural selection. Measuring cell survival and proliferation can therefore help researchers understand the evolutionary dynamics underlying therapeutic resistance.
3. Detecting resistant cells
Looking for resistant cells rather than sensitive cells
If researchers are looking only for therapeutic response or sensitivity, they may find a drug that results in shrinkage of the tumor, but if there are resistant cells, relapse will result. It is therefore necessary to know whether there are cells resistant to the therapy prior to application of that therapy in order to minimize the likelihood of relapse/therapeutic resistance
Collecting and analyzing a post-therapy sample
A post-therapy sample is necessary to determine how the cell population responded to the selective pressure of therapy.
In this paper, we assessed the extent to which evolutionary theory and methods have been used in research on therapeutic resistance and relapse in cancer.