BackgroundIt is unclear whether breast cancer (BC) subtypes or CSF cytology results are associated with overall survival (OS) among patients with BC leptomeningeal disease (LMD). This single-institution retrospective study compares OS among BC patients with LMD across various breast cancer subtypes and CSF cytology results. MethodologyThe study enrolled BC patients diagnosed with LMD between 2010-2023. Breast cancer subtypes were classified as A. ER+/HER2-, HER2+, or triple-negative BC (TNBC); B. HER2+, HER2-Low, HER2-Zero. CSF cytology subtypes included CSF+, CSF-, or CSF not tested (NT). OS was summarized via Kaplan-Meier analysis and compared using log-rank test. Cox models were used for multivariate analyses. ResultsOut of 69 patients registered, median OS (95% CI) for ER+/HER2- (n=33), HER2+ (n=12) and TNBC (n=24) subtypes were 8.0 (3.02, 24.8), 5.71 (1.61, not estimated) and 3.2 (1.11, 4.95) months (p=0.17). In multivariate analysis, TNBC was associated with worse OS vs ER+/HER2- [Hazard Ratio (HR), 95% CI: 2.64 1.23-5.80, p=0.04]. HER2 subtypes (HER2-Zero, n=21; HER2-Low, n=32; HER2+, n=12) showed no significant differences in OS. Median OS (95% CI) for CSF+ (n=16), CSF- (n=18), and CSF NT (n=35) groups were 3.54 (1.61, 12.72), 13.41 (4.95, 61.93) and 3.28 (1.44, 6.92) months (p=0.04). Multivariate analysis showed both CSF+ and CSF NT were associated with shorter OS compared to CSF- group [HR (95% CI) 4.50 (1.75, 12.11) for CSF+ vs CSF-; 2.91 (1.45, 6.26) for CSF NT vs CSF-; p=0.002]. ConclusionTNBC LMD group was associated with worse OS than ER+/HER2- BC LMD when adjusting for other prognostic factors. CSF- LMD patients had better OS than CSF+ or CSF NT LMD. Micro-abstractThis retrospective study investigated the association of receptor subtypes and CSF cytology results on the overall survival (OS) of breast cancer patients with leptomeningeal disease. Triple-negative breast cancer was associated with worse OS compared to ER+/HER2- breast cancer. A negative CSF cytology was associated with better OS than a positive cytology.