Evolutionary Dynamics of Treatment-Induced Resistance in Cancer Informs Understanding of Rapid Evolution in Natural Systems

Abstract

Rapid evolution is ubiquitous in nature. We briefly review some of this quite broadly, particularly in the context of response to anthropogenic disturbances. Nowhere is this more evident, replicated and accessible to study than in cancer. Curiously cancer has been late - relative to fisheries, antibiotic resistance, pest management and evolution in human dominated landscapes - in recognizing the need for evolutionarily informed management strategies. The speed of evolution matters. Here, we employ game-theoretic modeling to compare time to progression with continuous maximum tolerable dose to that of adaptive therapy where treatment is discontinued when the population of cancer cells gets below half of its initial size and re-administered when the cancer cells recover, forming cycles with and without treatment. We show that the success of adaptive therapy relative to continuous maximum tolerable dose therapy is much higher if the population of cancer cells is defined by two cell types (sensitive vs. resistant in a polymorphic population). Additionally, the relative increase in time to progression increases with the speed of evolution. These results hold with and without a cost of resistance in cancer cells. On the other hand, treatment-induced resistance can be modeled as a quantitative trait in a monomorphic population of cancer cells. In that case, when evolution is rapid, there is no advantage to adaptive therapy. Initial responses to therapy are blunted by the cancer cells evolving too quickly. Our study emphasizes how cancer provides a unique system for studying rapid evolutionary changes within tumor ecosystems in response to human interventions; and allows us to contrast and compare this system to other human managed or dominated systems in nature.