Leptomeningeal carcinomatosis in patients with breast cancer: a monocentric study

Background: Leptomeningeal metastasis represents one of the most severe complications of metastatic breast cancer and is associated with rapid neurological deterioration and poor prognosis. Over the past fifteen years, the therapeutic landscape has undergone significant transformation, with the introduction of novel systemic agents with meaningful CNS activity and the progressive refinement of locoregional treatment strategies. The objective of the present study is to describe clinicopathological characteristics, diagnostic approach, and treatment patterns of patients with leptomeningeal metastasis from breast cancer treated at a single institution, to evaluate temporal evolution of clinical presentation and therapeutic strategies across three consecutive time intervals, and to identify variables independently associated with overall survival in this population. Methods: This study evaluated patients with breast cancer diagnosed with leptomeningeal metastasis at Istituto Oncologico Veneto - IRCCS from 2010 to 2025. Based on year of leptomeningeal metastasis diagnosis, patients were divided into three groups: 2010-2015, 2016-2020, and 2021-2025. Hormone receptor (HR) and HER2 expression were evaluated by immunohistochemistry. Overall survival was defined as the time interval between leptomeningeal metastasis diagnosis and last follow-up or death. Results: The study included 159 patients diagnosed with leptomeningeal metastases from breast cancer. The biological subtype distribution was HR+/HER2- in 61.0% of patients, HER2+ in 25.2% and TNBC in 13.8%. Significant differences were observed across biological subtypes in time from stage IV diagnosis to leptomeningeal metastasis development (median 5.3 months in TNBC, 19.4 months in HER2+, and 21.9 months in HR+/HER2-, log-rank p<0.001), in presence of extracranial disease at diagnosis (81.8% in TNBC, 94.8% in HR+/HER2-, and 80% in HER2+, p=0.018), and in the use of systemic therapy after diagnosis (59.1% in TNBC, 74.2% in HR+/HER2-, and 87.5% in HER2+, p=0.041). At a median follow-up of 31.3 months (95% CI 23.9-38.8), 87.4% of patients had died. Median overall survival from leptomeningeal metastasis diagnosis was 2.99 months (95% CI 1.98-4.00). At multivariate analysis, variables independently 2 associated with a shorter overall survival were breast cancer subtype (TNBC having the worst prognosis, p=0.009), deteriorated performance status (p=0.002), not receiving systemic treatment (p<0.001) and not receiving radiotherapy after leptomeningeal metastasis diagnosis (p<0.001). Over the three time periods, we observed a significant increase in the proportion of patients presenting preserved performance status (p=0.006) and a significant decrease in the proportion presenting neurological symptoms at diagnosis (p=0.002). A significant shift in treatment patterns was observed, with intrathecal therapy use declining from 31.4% to 0% (p<0.001) and brain radiotherapy increasing from 20.0% to 60.3% (p=0.001). A significant improvement in overall survival was observed over the three time intervals (median OS 1.91, 2.20, and 5.06 months respectively, log-rank p=0.022). Conclusions: Despite the dismal prognosis associated with breast cancer-related leptomeningeal metastasis, outcomes have progressively improved over the last fifteen years. The strong prognostic impact of performance status and treatment use after diagnosis underscores the importance of timely recognition and therapeutic intervention before neurological and functional decline occur.