Abstract P6-17-02: Ado-trastuzumab emtansine (T-DM1) is effective against established HER2-positive breast cancer brain metastases in mice

Abstract

Abstract Background: Brain metastases represent a major problem in the treatment of HER2-positive breast cancer (1). The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases. Methods: We used previously established animal models of HER2-positive breast cancer brain metastases and organotypic brain slice cultures that recapitulate clinical scenarios (2). We treated mice bearing HER2-positive breast cancer brain metastases with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, gene expression, and HER2 downstream signaling. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven breast tumors. The activity of T-DM1 resulted in a striking survival benefit compared to trastuzumab (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, P<0.001). A comparison of T-DM1 with trastuzumab revealed no difference in their tumor distribution, HER2 downstream signaling inhibition or immune cell enrichment. T-DM1, however, led to a significant increase in tumor cell apoptosis. Electron microscopy studies revealed increased numbers of abnormal mitotic figures in brain tumors treated with T-DM1. Whole-transcriptome microarray analysis of BT474 brain tumors treated with trastuzumab or T-DM1 showed an enrichment of genes that are associated with mitotic catastrophe in the group treated with the antibody-drug conjugate. These mechanistic studies support the hypothesis that the efficacy of ado-trastuzumab emtansine in the brain microenvironment is mediated through the cytotoxic chemotherapeutic effect of the DM1 component. Conclusions: Our findings suggest that T-DM1 can overcome resistance to HER2-targeted therapies in the CNS, and warrants clinical investigation for the effective treatment of HER2-positive breast cancer brain metastases.