Development of Leptomeningeal Metastases in Breast Cancer Patients Receiving Stereotactic Radiosurgery

Abstract

Leptomeningeal metastases (LM) are a late stage manifestation of advanced breast cancer, associated with high morbidity and poor prognosis, and frequently managed with whole brain radiotherapy (WBRT) and/or intrathecal chemotherapy. A subset of breast cancer patients who undergo stereotactic radiosurgery (SRS) for limited brain metastases (BM) ultimately develop LM. Patients at high risk for development of LM within a short interval after SRS may benefit from a therapeutic switch from SRS to more comprehensive radiotherapy. We hypothesized that this subset of high-risk patients may be identified by patient, disease, and/or treatment parameters extracted from the electronic health record and treatment planning system. Clinical records from consecutive breast cancer patients from a single institution who underwent SRS for BM between February 2010 and March 2018 were retrospectively analyzed. The diagnosis of LM was determined by positive cerebrospinal fluid analysis and/or findings consistent with LM on MRI brain and/or spine as determined by a neuroradiologist. Demographic data, clinical history, breast cancer histopathology, BM features, systemic disease burden, and prior treatments were analyzed with Cox proportional hazards regression. A two-tailed p-value of less than 0.05 was considered statistically significant. We studied 135 breast cancer patients with BM who underwent SRS, of whom 22 (16.3%) later developed LM. With a median follow up of 18.9 (IQR 8.6-38.7) months after diagnosis of BM, the actuarial rate of LM at 18 months was 14.5% (7.0-21.4%, 95% CI). In those who developed LM, median time between their first SRS or most recent LM-free SRS to diagnosis of LM was 13.4 (IQR 4.6-22.9) or 5.3 (IQR 3.6-12.2) months, respectively. At the time of the most recent LM-free SRS, 9 (40.9%) and 5 (22.7%) patients had undergone prior surgical resection or WBRT, respectively, including one who had undergone both treatments. Median OS after diagnosis of LM was 7.3 (3.1-15.4, 95% CI) months. There was significantly increased risk of LM with ≥5 vs <5 BM at BM diagnosis (33.0% vs 7.5% [18-month actuarial risk], HR 3.5, p=0.0045), and ≥7 vs <7 cumulative number of BM treated (21.9% vs 11.1% [18-month actuarial risk], HR 2.7, p=0.023). Variables not significantly associated with the risk of LM in this dataset included tumor receptor status (ER, PR, Her2, triple negative), graded prognostic assessment, KPS, extracranial metastases, prior WBRT, or prior surgical . Patients with a larger number of brain metastases at BM diagnosis or ≥7 cumulative number of brain metastases treated appear to be at higher risk of developing LM and may benefit from stronger consideration of WBRT and/or brain-penetrating systemic therapy.