BSLD-04 TARGETING LEPTOMENINGEAL METASTASES IN HER2+ BREAST CANCER: A PRECLINICAL STUDY OF TRASTUZUMAB DERUXTECAN

Abstract

Leptomeningeal metastases (LM) are a severe and fatal complication of advanced HER2-positive breast cancer, with limited effective treatment options. Robust preclinical models are needed to better understand LM biology and to evaluate novel therapeutic strategies. We developed an athymic nude mouse model of LM using human HER2-positive JIMT1-BR3 breast cancer cells selected for leptomeningeal tropism (JIMT1-BR3-LM4). Leptomeningeal tumor progression was evaluated using bioluminescence imaging, magnetic resonance imaging, histopathology, and immunofluorescent analyses. Therapeutic efficacy of two doses of trastuzumab deruxtecan (T-DXd) was compared with trastuzumab, nab-paclitaxel, and trastuzumab plus nab-paclitaxel. Pharmacodynamic effects, drug distribution, lesion burden, and survival were assessed. Bulk RNA sequencing was performed to identify molecular alterations associated with leptomeningeal tropism. T-DXd demonstrated dose-dependent antitumor activity, with the higher dose producing marked reductions in leptomeningeal tumor burden in the brain and spine, as well as decreased lesion number, lesion size, and associated edema. T-DXd significantly reduced tumor cell proliferation and increased apoptosis within leptomeningeal lesions. Drug distribution to leptomeningeal lesions was comparable to, or slightly lower than, trastuzumab. T-DXd reduced both leptomeningeal and limited parenchymal brain metastases and produced similar pharmacodynamic effects in both compartments. Treatment with T-DXd significantly prolonged survival, with a subset of animals exhibiting durable long-term survival. Bulk RNA sequencing identified top pathway alterations, including cytokine–cytokine receptor interactions, calcium signaling, cell adhesion molecules, and TNF signaling. LINC01638, POSTN, and VCAM1 were identified as top differentially expressed genes. Validation of these genes is underway. These findings support clinical evaluation of T-DXd for HER2-positive LM and establish this model as a valuable platform for therapeutic discovery.