Patient-specific tumor growth trajectories determine persistent and resistant cancer cell populations during treatment with targeted therapies

The importance of preexisting versus acquired drug resis-would lead to very large preexisting populations of resistant tance in patients with cancer treated with small-molecule cells at the initiation of treatment. However, combining pre-tyrosine kinase inhibitors (TKI) remains controversial. The existing resistance with persister populations can explain the goal of this study is to provide a general estimate of the size and observed tumor volume trajectories and yields an estimated dynamics of a preexisting, drug-resistant tumor cell popula-preexisting resistant fraction varying from 10⁴ to 10¹ at the tion versus a slow-growing persister population that is the time of treatment initiation for this study cohort. Our results precursor of acquired TKI resistance. We describe a general also demonstrate that the growth rate of the resistant popu-model of resistance development, including persister evolu-lation is highly correlated to the time to tumor progression. tion and preexisting resistance, solely based on the macro-These estimates of the size of the resistant and persistent tumor scopic trajectory of tumor burden during treatment. We cell population during TKI treatment can inform combination applied the model to 20 tumor volume trajectories of treatment strategies such as multi-agent schedules or a com-EGFR-mutant lung cancer patients treated with the TKI erlo-bination of targeted agents and radiotherapy. tinib. Under the assumption of only preexisting resistant cells or only persister evolution, it is not possible to explain the Significance: These findings quantify pre-existing resistance observed tumor trajectories with realistic parameter values. and persister cell populations, which are essential for the integra-Assuming only persister evolution would require very high tion of targeted agents into the management of locally advanced mutation induction rates, while only preexisting resistance disease and the timing of radiotherapy in metastatic patients.