Abstract P3-03-01: Intracranial PDX models of breast cancer metastasis

Abstract

Abstract Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is an independent factor for development of brain metastases. Up to 37% of patients with HER2 positive disease relapse intracranially despite control of extra-cranial metastatic disease. Inability of anti-cancer agents to cross an intact blood-brain barrier (BBB) is a possible explanation for the increased incidence of brain metastases. Subcutaneous (SQ) patient-derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, orthotopic PDX models may confer a translational advantage as the patient tumor microenvironment is more closely mimicked. Especially when targeting brain tumors, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to develop a panel of intracranial PDX models of breast cancer brain metastases for pre-clinical efficacy studies of new anticancer drugs. Methods: SQ tumors from three different HER2 positive PDX breast cancer models designated ST340, ST1339 and ST1616B were enzymatically digested and used for intracranial stereotactic injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take. Intracranial tumor growth was monitored using MRI and positron emission tomography (PET) in conjunction with the amino acid radio tracer 18F-FET. Results: MRI confirmed tumor take in one model as early as 2 weeks after intracranial implantation. Increased 18F-FET uptake was detected in all models. MRI could be effectively used to monitor tumor growth and the corresponding 18F-FET PET images demonstrated increased 18F-FET uptake over time. Conclusion: Three different HER2 positive intracranial PDX breast metastases models were established from low passage SQ PDX models. We suggest, that using these intracranial PDX models of brain metastases, new drugs for advanced breast cancer can be evaluated in preclinical models that more closely mimic the microenvironment and the BBB in patients. In addition, translational imaging techniques can be evaluated during preclinical testing and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established SQ and orthotopic PDX models of breast cancer and brain metastases can be used as a relevant translational platform for testing of new drugs. Citation Format: Nielsen CH, Nedergaard MK, Wick MJ, Papadopoulos K, Tolcher AW, Kjaer A. Intracranial PDX models of breast cancer metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-01.