Abstract A011: Preclinical models of breast cancer brain metastasis for drug efficacy studies
Authors: Nielsen Carsten H. , Wick Michael J. , Kristensen Lotte K. , Joergensen Henriette S. , Alfsen Maria Z. , Juul Mark U. , Moriarty Alyssa , Papadopoulos Kyriakos P. , Kjaer Andreas 
Published: March 2020

Abstract
Background: Overall, 10-30% of patients with metastatic breast cancer (BC) will develop brain metastases. Depending on the subtype of the primary breast cancer the incidence of brain metastases varies ranging from 14% (hormone receptor positive BC) to 46% (triple-negative BC) and approximately about 34% for patients with HER2-positive BC. The major impact of the blood-brain-barrier (BBB), BBB efflux pumps and the local microenvironment in the brain represent a challenge for treatment of BC brain metastasis and treatment options remain limited. The aim of this study was to develop a model system of breast cancer brain metastases for evaluation of drugs directed at BC brain metastases. Methods: Models of BC brain metastasis were established by intracranial stereotactic injection of enzymatically digested PDX tumors (ST340, ST941, ST1339, ST1616B, ST1360B, and ST3338) or by intracardiac or intracarotid injection of cell suspensions in nude mice. Contrast-enhanced T1- and T2-weighted magnetic resonance imaging (MRI) or bioluminescence imaging was used to determine tumor take and growth. Drug sensitivity to single agent trastuzumab emtansine (T-DM1) administered intravenously were performed at confirmed tumor take in a subset of the models. Mice were treated with either saline or T-DM1, 10 mg/kg/week x4 or 2 mg/kg/week x4. PET imaging with 18F-FES was applied in estrogen receptor (ER) positive models as a PD biomarker of anti-estrogen receptor endocrine therapy. Results: T-DM1 treatment in the intracranial ST1339 or ST3338 HER2 positive (3+) PDX models inhibited tumor growth and prolonged survival compared to non-treated animals. However, T-DM1 treatment only caused a modest growth delay in the ST3338 model established intracranially compared to a complete response in the model established subcutaneously. Delivery of T-DM1 across the BBB to the intracranial tumors was visualized by 64Cu-trastuzumab PET/CT and high tumor uptake was associated with a response to T-DM1 therapy in the ST1339 model. Models of BC brain metastasis were successfully established by the intracardiac or intracarotid methods for the triple negative BC cell line MDA-MB-231, the HER2 positive cell line BT474, and an ER positive cell line (ST941C). In vivo imaging with 18F-FES PET/CT was able to visualize intracranial ER positive BC tumors, and animals treated with fulvestrant exhibited reduced 18F-FES tumor uptake. Conclusion: We have established model systems of BC brain metastasis and drug efficacy evaluation. Treatment response to T-DM1 was observed in intracranial HER2 positive models and delivery of T-DM1 to the tumors was visualized by 64Cu-trastuzumab PET/CT imaging. Together, the established breast cancer brain metastases models in combination with advanced non-invasive imaging can be used as a relevant translational platform for evaluation of new drugs.
Citation Format: Carsten H. Nielsen, Michael J. Wick, Lotte K. Kristensen, Henriette S. Joergensen, Maria Z. Alfsen, Mark U. Juul, Alyssa Moriarty, Kyriakos P. Papadopoulos, Andreas Kjaer. Preclinical models of breast cancer brain metastasis for drug efficacy studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A011. doi:10.1158/1535-7163.TARG-19-A011