Machine-learning and mechanistic modeling of primary and metastatic breast cancer growth after neoadjuvant targeted therapy

Abstract

Clinical trials involving systemic neoadjuvant treatments in breast cancer aim to shrink tumors prior to surgery while simultaneously allowing for controlled evaluation of biomarkers, toxicity, and suppression of distant (occult) metastatic disease. Yet such trials are rarely preceded by preclinical testing involving surgery. Here we used a mouse model of spontaneous metastasis after surgical removal to develop a predictive mathematical model of neoadjuvant treatment response to sunitinib, a receptor tyrosine kinase inhibitor (RTKI). Longitudinal data consisted of measurements of presurgical primary tumor size and postsurgical metastatic burden in 128 mice (104 for model training, 24 for validation), following variable neoadjuvant treatment schedules over a 14-day period. A nonlinear mixed-effects modeling approach was used to quantify inter-animal variability. Machine learning algorithms were applied to investigate the significance of several biomarkers at resection as predictors of individual kinetics. Biomarkers included circulating tumor- and immune-based cells (circulating tumor cells and myeloid-derived suppressor cells) as well as immunohistochemical tumor proteins (CD31 and Ki67). Our simulations showed that neoadjuvant RTKI treatment inhibits primary tumor growth but has little efficacy in preventing (micro)-metastatic disease progression after surgery. Surprisingly, machine-learning algorithms demonstrated only limited predictive power of tested biomarkers on the mathematical parameters. These results suggest that presurgical modeling might be an effective tool to screen biomarkers prior to clinical trial testing. Mathematical modeling combined with artificial intelligence techniques represent a novel platform for integrating preclinical surgical metastasis models in outcome prediction of neoadjuvant treatment. Major findingsUsing simulations from a mechanistic mathematical model compared with preclinical data from surgical metastasis models, we found anti-tumor effects of neoadjuvant RTKI treatment can differ between the primary tumor and metastases in the perioperative setting. Model simulations with variable drug doses and scheduling of neoadjuvant treatment revealed a contrasting impact on initial primary tumor debulking and metastatic outcomes long after treatment has stopped and tumor surgically removed. Using machine-learning algorithms, we identified the limited power of several circulating cellular and molecular biomarkers in predicting metastatic outcome, uncovering a potential fast-track strategy for assessing future clinical biomarkers by paring patient studies with identical studies in mice.