American Association for Cancer Research
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Supplementary Data from Patient-Specific Tumor Growth Trajectories Determine Persistent and Resistant Cancer Cell Populations during Treatment with Targeted Therapies

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posted on 2023-03-31, 02:28 authored by Clemens Grassberger, David McClatchy, Changran Geng, Sophia C. Kamran, Florian Fintelmann, Yosef E. Maruvka, Zofia Piotrowska, Henning Willers, Lecia V. Sequist, Aaron N. Hata, Harald Paganetti

This file contains supplemental figures 1-3. SF1: detailed description of sequential fitting process with example; SF2: relative uncertainties of the pre-existing resistant and persistent fractions; SF3: robustness analysis - results of the combined model for different mutation induction probabilities

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NCI

American Lung Association

National Natural Science Foundation of China

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ARTICLE ABSTRACT

The importance of preexisting versus acquired drug resistance in patients with cancer 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 preexisting, 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 preexisting 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 preexisting 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 preexisting resistance would lead to very large preexisting populations of resistant cells at the initiation of treatment. However, combining preexisting resistance with persister populations can explain the observed tumor volume trajectories and yields an estimated preexisting 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. These findings quantify pre-existing resistance and persister cell populations, which are essential for the integration of targeted agents into the management of locally advanced disease and the timing of radiotherapy in metastatic patients.

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