Abstract / Summary
Abstract Compared to hormone receptor (HR)-positive breast cancers, triple-negative and HER2+ subtypes demonstrate greater prevalence of central nervous system (CNS) metastasis, including its most aggressive form, leptomeningeal disease (LMD). In LMD, cancer cells infiltrate the leptomeninges of the brain and spine, resulting in rapid progression, with dismal prognosis and lack of effective treatment. In this retrospective analysis of 141 breast cancer patients with LMD treated at Stanford Hospital (2008–2020), we sought to provide a comprehensive evaluation of each HR (estrogen receptor (ER), progesterone receptor (PR)) and HER2 receptor status at multiple timepoints between primary diagnosis and CNS metastasis, with a particular focus on the impact of HR discordance events on disease outcomes. Receptor status was recorded at the primary tumor diagnosis, at subsequent local recurrence, non-CNS metastases, brain metastases and LMD. Linear and Cox regression analyses were performed to evaluate the impact of HR status and HR discordance between primary breast cancer and LMD on disease progression. HR status at local recurrences and distant metastases, assessed by immunohistochemistry and clinical notes, was incorporated as a time-dependent covariate. A systematic review and meta-analysis were performed to compare receptor status distributions and dynamics in the Stanford cohort with published CNS metastasis cohorts. For both ER and PR, negative HR status at primary breast cancer diagnosis was associated with higher CNS tropism, a shorter time to LMD diagnosis, and reduced survival following LMD diagnosis. Since initial diagnosis, receptor status switched in 29% (41 out of 141) of patients, with HRs switched in 26% (37/141) and HER2 switched in 7% (10/141) of patients. HR loss was a predominant change after initial diagnosis and was strongly associated with increased CNS tropism and LMD. Our results confirm the value of reassessing receptor status at recurrence and identify loss of ER or PR expression as a potential marker of CNS-directed disease progression that warrants further study.