BSLM-11 Establishing and Validating in Vivo Models for Leptomeningeal Metastases in Breast Cancer: Insights and Therapeutic Implications

Abstract Leptomeningeal metastases (LM), characterized by cancer cell growth in the linings of the brain and spinal cord, and the cerebrospinal fluid (CSF) compartment, have a dire prognosis represent 5-15% of central nervous system metastases. LM occur in all subclasses of breast cancer and are currently treated with intrathecal methotrexate or liposomal cytarabine or radiation therapy. Despite initial response to current treatments, median survival remains poor. Relatively little is known on the development of LM, due to the lack of adequate mouse models. This study aimed to develop and validate in vivo models of LM and to use them to credential potential therapies. Three breast cancer models were established using intracisternal injections of tumor cells covering the HER2+, ER+ lobular and triple negative breast cancer subtypes. The HER2+ model was produced from the JIMT-1-BR cell line that previously was enriched for metastasis to the brain parenchyma, reflecting clinical observations of concurrent parenchymal and LM spread. Multiple endpoints were implemented to assess disease progression: bioluminescence imaging, histopathology, MRI, tumor cells in CSF. Bulk RNA sequencing on all LM-tropic cell lines revealed significant alterations in cytokine-cytokine receptor interactions, calcium signaling pathways, cell adhesion molecules, and TNF signaling pathways across all models. Notably, several genes including PORCN, PGBD5, FAM43A and FHOD3 were differentially expressed and consistently alter across all models. Validation of these key genes is underway. For the JIMT-1-BR HER2+ model, efficacy studies compared standard therapy (trastuzumab + paclitaxel) with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). T-DXd (10 mg/kg, iv q3w) demonstrated superior efficacy with extended survival and reduced extent of edema on MRI. This study established and validated three in vivo models of LM colonization. These models, incorporating diverse endpoints, and drug testing capabilities, offer a valuable platform for identifying novel therapeutic strategies to combat this aggressive form of breast cancer progression.