Abstract PO5-06-01: Loss of hormone receptor expression in breast cancer is associated with increased brain tropism and accelerated progression of leptomeningeal disease
Authors: Pribus Sophia , Umeh-Garcia Maxine C. , Gu Bo , Godfrey Bryanna , Han Summer , Chernikova Sophia , Gephart Melanie Hayden 
Published: May 2024

Abstract
The four breast cancer subtypes—luminal A, luminal B, HER2-overexpressing, and triple-negative breast cancer (TNBC) – are classified based on gene expression profiles of hormone receptors (HRs) (estrogen receptor (ER) and progesterone receptor (PR)) and human epidermal growth factor receptor 2 (HER2/ERBB2).
Negative hormone receptor status is known to be associated with more aggressive breast cancer. Compared to other breast cancer subtypes, the HR-negative TNBC and HER2-overexpressing subtypes are characterized by high rates of recurrence and a notable increase in brain metastases and in particular, leptomeningeal disease (LMD). LMD – the most aggressive form of central nervous system (CNS) metastasis, in which cancer cells infiltrate leptomeninges of the brain and spine – carries a dismal prognosis due to a rapid progression, poor detection, and no effective treatment.
Several studies that investigated the link between HR status and LMD suggest that HR-negative breast cancers have a shorter time to LMD diagnosis. This shortened timeline is consistent with higher migratory capabilities reported for TNBC and HER2 breast cancer cells. However, as it is known that breast cancers exhibit subtype-specific metastatic tropism (i.e., luminal subtypes tend to metastasize to bone and liver, while TNBCs metastasize to the CNS), the longer time between primary breast cancer diagnosis and LMD diagnosis for HR-positive breast cancers may also reflect a longer metastatic route that first includes a non-CNS location.
In this study, we performed a retrospective analysis on 141 breast cancer patients with LMD treated at Stanford Hospital between 2008-2020. The Stanford LMD cohort was analyzed using linear regression analysis, Cox regression analysis, and Chi-squared analysis. HR status was recorded (when available) for local recurrences and distant metastases, and was included in our regression models as a time-dependent HR covariate. We tested if: (1) HR-negative breast cancers had shorter time between primary and LMD diagnosis as well as worse survival after LMD diagnosis versus HR-positive breast cancers, and if (2) HR loss (i.e., HR status changing from positive to negative) increased likelihood of the metastasis to CNS.
In agreement with published studies, the Stanford LMD cohort showed that HR-negative cancers had shorter time to development of LMD (p = 0.0004 for ER, p = 0.0001 for PR) and increased mortality following LMD (p = 0.010 for ER, p = 0.009 for PR). We found that HR-negative status at primary breast cancer diagnosis increased risk of first metastasis to CNS versus non-CNS locations (p = 0.021 for ER, p = 0.043 for PR). HR status switch (also known as hormone discordance) between primary diagnosis and metastasis occurred in 15% of patients in Stanford cohort, consistent with other studies. Importantly, accounting for HR status switch strengthened the association between HR-negative status and the risk of CNS metastasis [Hazard Ratio = 2.506 (1.395 - 4.500) for “baseline ER status” versus Hazard Ratio = 3.509 (1.890 - 6.515) for “time-dependent ER status”, Hazard Ratio = 2.420 (1.310 - 4.471) for “baseline PR status” versus Hazard Ratio = 3.407 (1.815 - 6.395) for “time-dependent PR status”].
In conclusion, HR-negative status was associated with shorter time to development of LMD, higher CNS tropism, and shorter survival following LMD diagnosis. Taking into consideration hormone discordance between the primary tumor and metastatic sites strengthened this association. Our results suggest a potential value in testing HR status at all recurrences and advanced CNS monitoring following HR loss.
Citation Format: Sophia Pribus, Maxine C. Umeh-Garcia, Bo Gu, Bryanna Godfrey, Summer Han, Sophia Chernikova, Melanie Hayden Gephart. Loss of hormone receptor expression in breast cancer is associated with increased brain tropism and accelerated progression of leptomeningeal disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-01.