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

The importance of pre-existing versus acquired drug resistance in cancer patients treated with small molecule tyrosine kinase inhibitors (TKI) remains controversial. The goal of this study is to provide a general estimate of the size and dynamics of a pre-existing, drug-resistant tumor cell population versus a slow-growing persister population that is the precursor of acquired TKI resistance. We describe a general model of resistance development, including persister evolution and pre-existing resistance, solely based on the macroscopic trajectory of tumor burden during treatment. We applied the model to 20 tumor volume trajectories of EGFR-mutant lung cancer patients treated with the TKI erlotinib. Under the assumption of only pre-existing resistant cells or only persister evolution, it is not possible to explain the observed tumor trajectories with realistic parameter values. Assuming only persister evolution would require very high mutation induction rates, while only pre-existing resistance would lead to very large pre-existing populations of resistant cells at the initiation of treatment. However, combining pre-existing resistance with persister populations can explain the observed tumor volume trajectories, and yields an estimated pre-existing resistant fraction varying from 10-4 to 10-1 at the time of treatment initiation for this study cohort. Our results also demonstrate that the growth rate of the resistant population is highly correlated to the time to tumor progression. These estimates of the size of the resistant and persistent tumor cell population during TKI treatment can inform combination treatment strategies such as multi-agent schedules or a combination of targeted agents and radiotherapy.