Murine breast cancer mastectomy model that predicts patient outcomes for drug development

Abstract

Background: Despite massive expenditures in preclinical studies, many breast cancer agents show efficacy in murine models but fail in human trials. In humans, metastatic disease determines survival, but preclinical murine models only evaluate drug efficacy against the primary tumor. We hypothesized that evaluating efficacy against metastatic breast cancer would more efficiently predict efficacy in a murine model than evaluating the primary tumor alone. This study (1) critically evaluated a murine tumor removal model with metastatic tumor burden quantification for breast cancer preclinical trials and (2) validated the model with an agent that previously passed preclinical trials but failed human trials.

Materials and methods: Tumorectomy and Halsted (radical) mastectomy procedures after inoculation of 4T1-luc2 cells were compared. The effect of AZD0530, an oral Src inhibitor that passed preclinical trials but failed human trials, was evaluated using an inoculation model with/without Halsted mastectomy.

Results: Significant amounts of residual disease were confirmed by bioluminescence (P = 0.003) and 100% developed local recurrence after tumorectomy versus 14% (P = 0.005) after Halsted mastectomy. Bioluminescence value at 15 min after luciferin injection highly correlated with peak except for 24 h after injection. AZD0530 significantly suppressed primary tumor burden compared with no treatment (P = 0.002); but not in lung metastases. In a Halsted mastectomy model, AZD0530 had no efficacy against lung metastases or difference in survival.

Conclusions: We critically evaluated and established a murine mastectomy model to evaluate metastatic tumors. It provides a new model for preclinical drug development that mimics the human adjuvant setting.

Keywords: Breast cancer; Drug development; Mastectomy; Metastasis; Model; Mouse.

Figure 1

The procedure of tumorectomy.

Figure 2

The procedure of Halsted mastectomy.

Figure 3

Two procedures for mastectomy were compared: (A) Resected tumor weight, (B) bioluminescence 24 hours after implantation and (C) recurrence rate within 30 days after implantation. Data are expressed as means ± SEM.

Figure 4

The time required to reach peak value and the peak value of bioluminescence in the orthotopic model and mastectomy model. (A) The time required to reach peak value in the orthotopic model and mastectomy model with or without AZD0530 treatment. Correlation of peak value and 15minute bioluminescence in the orthotopic model (B) and mastectomy model (C).

Figure 5

Whole body bioluminescence of AZD0530 treated orthotopic model. Tumor burden which mainly reflected primary tumor quantified by IVIS. Data are expressed as means ± SEM. *: p < 0.05.

Figure 6

Lung metastasis of AZD0530 treated orthotopic model. (A) Lung ex vivo. (B) H&E staining of lung metastases. Data are expressed as means ± SEM. *: p < 0.05.

Figure 7

AZD0530 treatment in mastectomy model. (A) Tumor burden which mainly reflected lung metastasis quantified by IVIS. (B) Survival of AZD0530 or vehicle treated mice. Data are expressed as means ± SEM.