Model-based analysis for investigating the impact of tumor size, lymphocyte and neutrophil on the survival of breast cancer 4T1 tumor-bearing mice

Survival is one of the foremost endpoints in cancer therapy, and parametric survival analysis could comprehensively demonstrate the overall result of various different baseline and longitudinal factors. In this study, the survival of triple negative breast cancer 4T1 tumor-bearing mice treated by gemcitabine (GEM) and dexamethasone (DEX) was investigated with model-based analysis. The tumor size, lymphocyte (LY) and neutrophil (NE) of 4T1 tumor-bearing BALB/c mice were collected, and the PK/PD models of these longitudinal data were established in a sequential manner, respectively. The parametric time-to-event (TTE) model of survival was developed and the PK/PD models were tested and integrated as time-varying prognostic factors. The final model was evaluated and externally validated. LY and NE influence the survival directly, while tumor size showed its indirect impact on survival by affecting LY. The exposure of GEM significantly improved the survival results but DEX did not bring extra benefit. The models established in this study quantitatively characterized the abnormal increasing of LY and NE due to tumor progression in T1 tumor-bearing mice and also demonstrate their relationship with survival outcomes, and further provide a modeling framework to demonstrate potential prognostic factors of survival and evaluate the efficacy of different therapies.