Search

Background Leptomeningeal disease (LMD) is a relatively uncommon manifestation of advanced cancer. Patients with LMD carry a poor prognosis and often decline rapidly, complicating inclusion in clinical trials. Identification of LMD subsets of greater incidence and more favorable prognosis might facilitate dedicated clinical trials in the future. We hypothesized that patients with breast cancer may represent such a population and sought to assess the relative incidence and prognosis of LMD secondary to breast vs. non-breast primaries. Methods We identified 2411 patients with intracranial metastases secondary to breast (N = 501) and non-breast (N = 1910) primaries at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 1996 and 2020, of whom 112 presented with and an additional 161 subsequently developed LMD. A log-rank test and Cox modeling were used to compare outcomes in patients with breast vs. non-breast primaries. Results Among patients with newly diagnosed intracranial disease, the incidence proportion of concurrent LMD was 11.4% vs. 2.9% among patients with breast vs. non-breast primaries (P Conclusions Patients with breast cancer and LMD may represent an ideal population for clinical trials given the higher incidence and potentially more favorable prognosis seen in this population.

Background Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD). Methods This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer. Results Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2–19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2–20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. Conclusion This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.

Brain metastases occur commonly in patients with advanced solid malignancies. Yet, less is known about brain metastases than cancer-related entities of similar incidence. Advances in oncologic care have heightened the importance of intracranial management. Here, in this consensus review supported by the Society for Neuro-Oncology (SNO), we review the landscape of brain metastases with particular attention to management approaches and ongoing efforts with potential to shape future paradigms of care. Each coauthor carried an area of expertise within the field of brain metastases and initially composed, edited, or reviewed their specific subsection of interest. After each subsection was accordingly written, multiple drafts of the manuscript were circulated to the entire list of authors for group discussion and feedback. The hope is that the these consensus guidelines will accelerate progress in the understanding and management of patients with brain metastases, and highlight key areas in need of further exploration that will lead to dedicated trials and other research investigations designed to advance the field.

Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive LMD.This multicenter study enrolled 34 LMD patients in a combined Phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the Phase I; the Phase II was limited to HER2-positive breast cancer.Intrathecal trastuzumab was well tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended Phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for Phase 2 dose treated patients was 8.3 months (95% CI 5.2 to 19.6). The Phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2 to 20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable CSF concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations.This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.