Balancing Efficacy and Toxicity in Treatment Delivery in HER2-Positive Breast Cancer

By: Vanessa A. Carter, BS
Posted: Tuesday, May 3, 2022

Ernesto A.B.F. Lima, PhD, of The University of Texas at Austin, and colleagues previously established a murine model of human HER2-positive breast cancer and evaluated whether the order in which trastuzumab and doxorubicin are delivered would affect treatment outcome. The study authors proposed their complete framework for selection, development, calibration, and treatment optimization to identify a proper protocol for HER2-positive breast cancer using a trastuzumab/doxorubicin combination during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 5050).

“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,” stated the investigators. “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.”

The study authors designed a family of 10 mathematical and in vivo models that characterized the dynamics of tumor-drug and drug-drug interactions. Each model was calibrated using a Bayesian framework, and the most sparing model was selected to represent the system. Additionally, optimal control theory was applied to determine which treatment protocol would be best for the selected model.

This study revealed two major findings. First, the total dose of both drugs was fixed to what was allocated in previous experiments, a treatment schema where the tumors demonstrated complete regression was identified, which did not increase the overall amount of therapy. Second, the treatment protocol with the least amount of drug administered (decreased by 58%) ultimately resulted in the same tumor kinetics as the experimental findings.

“Predictions can now be tested experimentally,” suggest the study authors. “This has a significant impact for the design of combination therapy for HER2-positive breast cancer.”

Disclosure: The study authors reported no conflicts of interest.

AACR Annual Meeting 2022

---