Factors improving 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 (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-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 2016-2020 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.

Conclusions: Increasing 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.

Figure 1

A) Total number of BC-LMD cases seen at Moffitt Cancer Center between 2011–2020, by breast cancer subtype. B) The proportion of BC-LMD patients to total breast cancer patients seen at Moffitt Cancer Center between 2011–2015 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). Abbreviations: Hormone Receptor Positive (HR+); Human Epidermal Growth Factor Receptor 2-Positive (HER2+); Triple Negative Breast Cancer (TNBC); Breast Cancer Leptomeningeal Disease (BC-LMD).

Figure 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). Abbreviations: Hormone Receptor Positive (HR+); Human Epidermal Growth Factor Receptor 2-Positive (HER2+); Triple Negative Breast Cancer (TNBC); Leptomeningeal Disease (LMD); Whole Brain Radiation Therapy (WBRT).

Figure 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). Abbreviations: Hormone Receptor Positive (HR+); Human Epidermal Growth Factor Receptor 2-Positive (HER2+); Triple Negative Breast Cancer (TNBC); Leptomeningeal Disease (LMD); Whole Brain Radiation Therapy (WBRT); Intrathecal (IT); Hazard Ratio (HR); Confidence Interval (CI).

Figure 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<.05, respectively). Compared to WBRT alone, patients receiving WBRT + systemic therapy or WBRT + systemic therapy + IT therapy had a significantly longer median OS (p<.0001, respectively). Abbreviations: Breast Cancer Leptomeningeal Disease (BC-LMD); Overall Survival (OS); Intrathecal Therapy (IT); Whole Brain Radiation Therapy (WBRT).