Improving mathematical models of cancer by including resistance to therapy: a study in non-small cell lung cancer

Abstract

We examined a dataset of 590 Non-Small Cell Lung Cancer patients treated with either chemotherapy or immunotherapy using a game-theoretic model that includes both the evolution of therapy resistance and a cost of resistance. We tested whether the game-theoretic model provides a better fit than classical mathematical models of population growth (exponential, logistic, classic Bertalanffy, general Bertalanffy, Gompertz, general Gompertz). To our knowledge, this is the first time a large clinical patient cohort (as opposed to only in-vitro data) has been used to apply a game-theoretic cancer model. The game-theoretic model provided a better fit to the tumor dynamics of the 590 Non-Small Cell Lung Cancer patients than any of the non-evolutionary population growth models. This was not simply due to having more parameters in the game-theoretic model. The game-theoretic model was seemingly able to fit more accurately patients whose tumor burden exhibit a U-shaped trajectory over time. We explained how this game-theoretic model provides predictions of future tumor growth based on just a few initial measurements. Using the estimates for treatment-specific parameters, we then explored alternative treatment protocols and their expected impact on tumor growth and patient outcome. As such, the model could possibly be used to suggest patient-specific optimal treatment regimens with the goal of minimizing final tumor burden. Therapeutic protocols based on game-theoretic modeling can help to predict tumor growth, and could potentially improve patient outcome in the future. The model invites evolutionary therapies that anticipate and steer the evolution of therapy resistance.