Factors associated with overall survival in breast cancer patients with leptomeningeal disease (LMD): a single institutional retrospective review

Abstract

Background: Breast 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 from 2011 to 2020, to determine the changing incidence of BC-LMD, factors which are associated with the progression of BC CNS metastasis to BC-LMD, and factors which are associated with OS for patients with BC-LMD.

Methods: Patients 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.

Results: 128 cases of BC-LMD were identified. The proportion of BC-LMD to total BC patients was higher between 2016 and 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) was associated with prolonged progression to LMD in all patients. Hormone therapy in patients with HR + BC were associated with a delayed BC-CNS metastasis to LMD progression. Lapatinib treatment was associated with a 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 was associated with prolonged survival for all patients. Lapatinib and trastuzumab therapy was associated with improved OS in patients with HER2 + BC-LMD.

Conclusions: Increasing rates of BC-LMD provide treatment challenges and opportunities for clinical trials. Prospective trials testing lapatinib and/or similar tyrosine kinase inhibitors, IT therapies, and combination treatments are urgently needed.

Fig. 1

A Total number of BC-LMD cases seen at Moffitt Cancer Center between 2011 and 2020, by breast cancer subtype. B The proportion of BC-LMD patients to total breast cancer patients seen at Moffitt Cancer Center between 2011 and 2015 and 2016–2020. A significantly higher proportion of (BC-LMD patients)/(Total Breast Cancer Patients) was observed in the latter half of the decade (p = 0.0168). HR + Hormone Receptor Positive; HER2 + Human Epidermal Growth Factor Receptor 2-Positive; TNBC Triple Negative Breast Cancer; BC-LMD Breast Cancer Leptomeningeal Disease

Fig. 2

Kaplan–Meier estimates for factors affecting time between CNS-metastasis diagnosis and BC-LMD diagnosis. A Patients with TNBC experienced a significantly shorter median time between breast cancer CNS-metastasis diagnosis and BC-LMD (4.3 months) compared to HR + (9.1 months) and HER2 + (10.5 months) patients. B Patients that received systemic therapy experienced a longer median time between CNS metastasis and BC-LMD (12.5 months) than patients who did not receive any systemic therapy (4.3 months). C Patients that received WBRT had a longer median time between their CNS metastasis and BC-LMD diagnosis (14.1 months) compared to patients that did not receive WBRT (5.3 months). HR + Hormone Receptor Positive; HER2 + Human Epidermal Growth Factor Receptor 2-Positive; TNBC Triple Negative Breast Cancer; LMD Leptomeningeal Disease; WBRT Whole Brain Radiation Therapy

Fig. 3

Kaplan–Meier estimate for factors affecting overall survival in BC-LMD patients. A TNBC-LMD patients had a significantly lower overall survival (2 months) when compared to HR + BC-LMD patients (5.3 months) and HER2 + BC-LMD patients (8.4 months). Median survival time between HR + and HER2 + BC-LMD patients did not significantly differ. B Patients receiving systemic therapy post BC-LMD diagnosis had a significantly higher median survival time (7.9 months) when compared to BC-LMD patients that did not receive systemic therapy (1.8 months). C Patients receiving intrathecal therapy post BC-LMD diagnosis had a significantly higher median survival time (11.8 months) when compared to BC-LMD patients that did not receive intrathecal therapy (1.9 months). D, E More specifically, overall survival median times were higher in patients that received intrathecal methotrexate (8.4 months) and/or intrathecal thiotepa (12 months) versus those that did not (2.9 months; 3.6 months, respectively). F patients receiving WBRT post BC-LMD diagnosis had a higher overall survival median time (6.5 months) than those who did not receive WBRT (2.7 months). HR + Hormone Receptor Positive; HER2 + Human Epidermal Growth Factor Receptor 2-Positive; TNBC Triple Negative Breast Cancer; LMD Leptomeningeal Disease; WBRT Whole Brain Radiation Therapy; IT Intrathecal; HR Hazard Ratio; CI Confidence Interval

Fig. 4

Kaplan Meier analysis of BC-LMD patients receiving different combinations of WBRT, Systemic Therapy, and/or IT therapy. Patients receiving only IT, systemic + IT, WBRT + IT, WBRT + systemic therapy, or all three therapies had a significantly longer median OS than patients that received no therapy (p < 0.05, respectively). Compared to WBRT alone, patients receiving WBRT + systemic therapy or WBRT + systemic therapy + IT therapy had a significantly longer median OS (p < 0.0001, respectively). BC-LMD Breast Cancer Leptomeningeal Disease; OS Overall Survival; IT Intrathecal Therapy; WBRT Whole Brain Radiation Therapy