BackgroundBreast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5–8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center (MCC) from 2011–2020, to determine the changing incidence of BC-LMD, which factors impact progression of BC CNS metastasis to BC-LMD, and which factors affect OS for patients with BC-LMDMethodsPatients with BC and brain/spinal metastatic disease were identified. For those who eventually developed BC-LMD, we used Kaplan-Meier survival curve, log-rank test, univariable, and multivariate Cox proportional hazards regression model to identify factors affecting time from CNS metastasis to BC-LMD and OS.Results128 cases of BC-LMD were identified. The proportion of BC-LMD to total BC patients was higher between 2016–2020 when compared to 2011–2015. Patients with HR + or HER2 + BC experienced longer times between CNS metastasis and LMD than patients with triple-negative breast cancer (TNBC). Systemic therapy and whole-brain radiation therapy (WBRT) prolonged progression to LMD in all patients. Hormone therapy in patients with HR + BC delayed BC-CNS metastasis to LMD progression. Lapatinib delayed progression to LMD in patients with HER2 + BC. Patients with TNBC-LMD had shorter OS compared to those with HR + and HER2 + BC-LMD. Systemic therapy, intrathecal (IT) therapy, and WBRT prolonged survival for all patients. Lapatinib and trastuzumab improved OS in patients with HER2 + BC-LMD.ConclusionsIncreasing rates of BC-LMD provide treatment challenges and opportunities for clinical trials. Trials testing lapatinib and/or similar tyrosine kinase inhibitors, IT therapies, and combination treatments are urgently needed.