Abstract P4-06-12: Murine radical mastectomy model for preclinical study of adjuvant systemic therapies

Abstract

Abstract Background: Current standard of care of breast cancer is removal of primary tumor followed by systemic adjuvant therapy to reduce recurrence and to prolong survival. However, vast majority of the preclinical studies that use murine models evaluate the drug response of primary tumors either in mammary pads or subcutaneous tissues. Lately it has been shown that the genetic profiles of metastatic lung tumors are significantly different from that of their primary mammary tumors, let alone subcutaneous tumors. Therefore we hypothesized that the responses of metastatic tumors rather than primary mammary tumors need to be evaluated for a systemic therapy. However there are few reports of murine mastectomy models used for preclinical study. Methods: Murine mammary adenocarcinoma 4T1-luc2 cells were inoculated into #2 right mammary fat pad under direct vision as previously described (Katsuta et al, JSR 2016). The tumor burden was quantified by bioluminescence IVIS imaging system. Novel platinum drug, Triplatin, or Vehicle was administrated every 4 days for 3 times from the day after inoculation. Amount of lung metastases were quantified ex vivo by IVIS imaging. Then we compared the growth of metastatic tumors between two methods of radical mastectomy; midline incision method and Halsted incision method, which were performed 8 days after inoculation. Triplatin or Vehicle was administered 2 days after mastectomies. Results: First we compared the two methods of chest mammary tumor removal; midline incision method and Halsted incision method. There was no significant difference in weight of resected tumors between these two techniques (p=0.751), however, the bioluminescence in midline incision model was significantly higher than Halsted incision model at the first day after operations (p=0.003). Only 1 out of 7 cases (14%) after Halsted incision method developed local recurrence, whereas all (100%) the animals that underwent midline incision method developed recurrence within 30 days after operation (p<0.001). No mice developed respiratory failure due to wound closure of wide skin defect. We then examined the effect of Triplatin on chest mammary tumor and lung metastasis. There was no significant difference in bioluminescence from chest mammary tumors between treatment group and non-treatment, however, ex vivo bioluminescence of lung metastases demonstrated that treatment group mice had significantly less tumor burden in lung than non-treatment group. Utilizing Halsted incision method with less local recurrence, we found that lung metastases were significantly less in treatment group than non-treatment group in live animals monitored by bioluminescence. Conclusion: We have established an improved murine chest mammary tumor resection model. Effects on metastases, as opposed to primary tumor should be evaluated for the preclinical study of adjuvant systemic therapy, since they may not be the same. Citation Format: Katsuta E, Takabe K. Murine radical mastectomy model for preclinical study of adjuvant systemic therapies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-12.