Abstract A011: HER2-positive PDX model of breast cancer brain metastasis obtained from patient prior to T-DM1 therapy
Authors: Nielsen Carsten H. , Wick Michael J. , Gamez Lizette , Knudsen Camilla S. , Jense Mette M. , Rundle Melissa , Papadopoulos Kyriakos P. , Kjaer Andreas 
Published: August 2018

Abstract
Background: Ado-trastuzumab emtansine (T-DM1), a recently approved antibody-drug conjugate (ADC), is approved for treatment of high HER2-expressing (3+), trastuzumab-resistant breast and gastric cancers. While this agent is effective, HER2-positive breast cancer patients have a high risk of brain relapse, seen in up to 37% of patients of whom half die as a result of failure to control the intracranial disease. The aim of this study was to develop a model system that reflects the breast cancer brain metastases seen in patients undergoing T-DM1 therapy. We collected brain metastasis tissue from an HER2-positive breast cancer patient prior to receiving T-DM1 therapy. Methods: The high HER2-expressing (3+) breast cancer brain metastasis model designated ST3338 was established subcutaneously in athymic nude mice using biopsy material from a brain metastasis obtained from a 42-year-old breast cancer patient. The patient was on T-DM1 therapy following sample collection and had received prior treatment with trastuzumab, bevacizumab, and lapatinib. Immunohisotochemistry of both clinical and PDX tissues was applied to assess the estrogen (ER), progesterone (PR), and HER2 receptor levels. Drug sensitivity studies were performed in the ST3338 model established subcutaneously in athymic nude mice to single-agent T-DM1 administered intravenously as a single dose at 10 mg/kg. The ST3338 was also established orthotopically by stereotactic intracranial inoculation of enzymatically digested ST3338 tumor tissue. Tumor development was monitored by T2-weighted MR imaging and the study endpoint was survival by humane endpoints. Results: Immunohistochemistry of PDX tissues was scored as ER (0), PR (0), and HER2 (3+), which corresponded to the clinical brain metastasis sample: ER (0), PR (0), and HER2 (3+). A single dose of T-DM1 at 10 mg/kg showed tumor regression compared with Day 0 (T/C = 0%) in the subcutaneous setting. The ST3338 model was successfully established orthotopically determined by longitudinal T2-weighted MR imaging, and efficacy data of T-DM1 in the orthotopic/intracranial setting are pending. 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 subcutaneous setting. With the combination of subcutaneous and intracranial PDX models of breast cancer brain metastases, new drugs can be tested in preclinical models that more closely mimic the microenvironment and the challenges of drug delivery across the blood-brain barrier in breast cancer patients.
Citation Format: Carsten H. Nielsen, Michael J. Wick, Lizette Gamez, Camilla S. Knudsen, Mette M. Jense, Melissa Rundle, Kyriakos P. Papadopoulos, Andreas Kjaer. HER2-positive PDX model of breast cancer brain metastasis obtained from patient prior to T-DM1 therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A011.