Abstract A15: Efficacy of trastuzumab emtansine (T-DM1) in subcutaneous and intracranial patient derived xenograft models of breast cancer metastasis
Authors: Nielsen Carsten H. , Nedergaard Mette K. , Kristensen Lotte K. , Knudsen Camilla S. , Wick Michael J. , Papadopoulos Kyri , Tolcher Anthony W. , Kjaer Andreas 
Published: May 2016

Abstract
Background: It is estimated that 10-30% of all breast cancer patients at some point develop brain metastases. Overexpression of the human epidermal growth factor receptor 2 (HER2) is a independent risk factor for development of brain metastases. Up to 37% of patients with HER2-positive metastatic breast cancer develop brain metastases and half of these patients die as a result of failure to control the intracranial disease. A reason for this is the challenge of efficient drug delivery across the blood brain barrier (BBB).
Subcutaneous patient derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, when targeting brain tumors or metastases, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to compare the efficacy of trastuzumab emtansine (T-DM1) in a HER2 positive breast cancer PDX model established subcutaneously and as an intracranial brain metastases model.
Methods: Mice were implanted subcutaneously with the HER2 positive breast cancer PDX model designated ST1339 and randomized into 3 treatment arms: Control, T-DM1 (5 mg/kg/week x4) and T-DM1 (10 mg/kg/week x4). Treatment response of subcutaneous tumors was monitored by caliper measurements. The intracranial PDX model was established by stereotactic intracranial injection of enzymatically digested ST1339 tumor tissue. At confirmed tumor take, mice were randomized into two arms: Control and T-DM1 (10 mg/kg/week x4). Treatment response was monitored by contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) and positron emission tomography (PET) with the amino acid radiotracer O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET).
Results: T-DM1 at 10 mg/kg/week x4 effectively inhibited tumor growth in the subcutaneous model whereas treatment with 5 mg/kg/week x4 did not have any effect on tumor growth. T-DM1 treatment at 10 mg/kg/week x4 of mice with intracranial tumors inhibited tumor growth and prolonged survival compared to non-treated animals.
Conclusion: A treatment response to T-DM1 was observed in both the subcutaneous and intracranial ST1339 HER2 positive breast cancer PDX model. With the combination of subcutaneous and intracranial PDX models of breast cancer and breast cancer brain metastases new drugs can thus be tested in preclinical models that more closely mimic the microenvironment and the challenges of drug delivery across the BBB in patients.
Citation Format: Carsten H. Nielsen, Mette K. Nedergaard, Lotte K. Kristensen, Camilla S. Knudsen, Michael J. Wick, Kyri Papadopoulos, Anthony W. Tolcher, Andreas Kjaer. Efficacy of trastuzumab emtansine (T-DM1) in subcutaneous and intracranial patient derived xenograft models of breast cancer metastasis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A15.