Abstract 2174: Intracranial PDX models of breast cancer brain metastases and PET imaging for drug efficacy studies

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.2174-2174
• Main Authors: Nielsen, Carsten H., Wick, Michael J., Jensen, Mette M., Kristensen, Lotte K., Moriarty, Alyssa, Rundle, Melissa, Papadopoulos, Kyriakos P., Kjaer, Andreas
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-2174

Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) is an independent risk factor for development of brain metastases. Between 37-55% of patients with HER2-positive metastatic breast cancer develop brain metastases and the incidence is increasing. A reason for the increase of brain metastases is the improved control of systemic disease by novel therapeutics such as ado-trastuzumab emtansine (T-DM1). However, 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 brain metastases. The aim of this study was to develop a model system of HER2 positive breast cancer brain metastases for evaluation of drugs directed at brain metastases. Methods: Subcutaneous tumors from a panel of HER2-positive PDX breast cancer models designated ST340, ST1339, ST1616B, ST1360B and ST3338 were enzymatically digested and used for intracranial stereotactic injection or intra carotid injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take and growth. Drug sensitivity studies to single agent 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. Delivery of T-DM1 to the tumor site was evaluated by PET/CT imaging with 64Cu-trastuzumab. Results: Intracranial tumor growth was detected by MR imaging in all models. T-DM1 treatment of animals with intracranial ST1339 or ST3338 tumors inhibited tumor growth and prolonged survival compared to non-treated animals. A variable response within the treatment groups was observed. 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. Conclusion: We have established a model system for evaluating drug sensitivity in HER2 positive breast cancer brain metastases. Treatment response to T-DM1 was observed in the models. 64Cu-trastuzumab PET imaging confirmed delivery of trastuzumab to the tumors, and high uptake was associated with an increased response to T-DM1 therapy. Together, the established PDX models of breast cancer and brain metastases can be used as a relevant translational platform in combination with advanced non-invasive imaging for evaluation of new drugs. Citation Format: Carsten H