Abstract 5050: Optimizing delivery of combination targeted and chemotherapy in a murine model of HER2+ breast cancer
Authors: Lima Ernesto A.B.F. , Wyde Reid , Sorace Anna G. , Yankeelov Thomas E. 
Published: June 2022

Abstract
The combination of targeted therapy to the human epidermal growth factor receptor 2 (HER2) and chemotherapy in HER2+ breast cancer is known to increase time to progression, duration of response, and survival rates. Previously, we established a murine model of human HER2+ breast cancer, and investigated whether the sequence in which two drugs are delivered affected the treatment outcome [1]. However, this combination therapy can cause cardiac toxicity. While the cardiac damage induced by trastuzumab does not appear to be dose dependent and it is reversible, doxorubicin cardiotoxicity is cumulative, dose dependent, and irreversible. Thus, rigorously identifying a treatment protocol that simultaneously maintains tumor control and reduces the total dose of doxorubicin, would potentially decrease the side effects experienced by patients receiving these treatments, while maintaining high treatment efficacy.
We propose a complete framework for model development, calibration, selection, and treatment optimization to find the optimal treatment protocol for HER2+ breast cancer using a trastuzumab-doxorubicin combination. To do so, we constructed a family of ten mathematical models designed to characterize the dynamics of tumor growth and treatment response. In particular, the models included tumor-drug and drug-drug interactions. Using a Bayesian framework, each of these models were calibrated to the data obtained in [1], and the most parsimonious model as determined by the Bayesian information criterion was selected to represent the system. We then applied optimal control theory (while considering uncertainty in the model parameters) to systematically identify the optimal treatment protocol using the selected model. We had two major findings. First, we kept the total dose of both drugs fixed to that which was employed in the experiments in [1], and identified a treatment schema where the tumors showed complete regression without increasing the overall amount of therapy. Then, we found the treatment schema with the least amount of drug delivered (decreased by 58%) that resulted in the same tumor kinetics as the experimental results.
Thus, we employed mathematical modeling and an in vivo model of breast cancer to rigorously and systematically identify treatment protocols that can improve tumor control with the same total dose, or achieve the same tumor control with less than half the doxorubicin dose. Predictions can now be tested experimentally. This has a significant impact for the design of combination therapy for HER2+ breast cancer.
[1] Sorace, A.G., Quarles, C.C., Whisenant, J.G., Hanker, A.B., McIntyre, J.O., Sanchez, V.M. and Yankeelov, T.E., 2016. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results. Breast cancer research and treatment, 155(2), pp.273-284.
Citation Format: Ernesto A.B.F. Lima, Reid Wyde, Anna G. Sorace, Thomas E. Yankeelov. Optimizing delivery of combination targeted and chemotherapy in a murine model of HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5050.