Integrative In Vivo Drug Testing Using Gene Expression Signature and Patient-Derived Xenografts from Treatment-Refractory HER2 Positive and Triple-Negative Subtypes of Breast Cancer

Abstract

Patient-derived xenografts (PDXs) are powerful tools for translational cancer research. Here, we established PDX models from different molecular subtypes of breast cancer for in vivo drug tests and compared the histopathologic features of PDX model tumors with those of patient tumors. Predictive biomarkers were identified by gene expression analysis of PDX samples using Nanostring nCount cancer panels. Validation of predictive biomarkers for treatment response was conducted in established PDX models by in vivo drug testing. Twenty breast cancer PDX models were generated from different molecular subtypes (overall success rate, 17.5%; 3.6% for HR+/HER2−, 21.4% for HR+/HER2+, 21.9% for HR−/HER2+ and 22.5% for triple-negative breast cancer (TNBC)). The histopathologic features of original tumors were retained in the PDX models. We detected upregulated HIF1A, RAF1, AKT2 and VEGFA in TNBC cases and demonstrated the efficacy of combined treatment with sorafenib and everolimus or docetaxel and bevacizumab in each TNBC model. Additionally, we identified upregulated HIF1A in two cases of trastuzumab-exposed HR−/HER2+ PDX models and validated the efficacy of the HIF1A inhibitor, PX-478, alone or in combination with neratinib. Our results demonstrate that PDX models can be used as effective tools for predicting therapeutic markers and evaluating personalized treatment strategies in breast cancer patients with resistance to standard chemotherapy regimens.