Incidence and outcomes of brain metastasis in ER-low breast cancer: Insights from a National Cancer Database (NCDB)

Background: Brain metastases (BrM) are aggressive and life-limiting complications that occur more frequently in triple-negative and HER2-positive breast cancers. The optimal cut-off value of estrogen receptor (ER) positivity has been under discussion for over a decade. Emerging data suggest that ER-low (1-10% ER staining) breast cancers exhibit clinical and biological features closer to ER-negative tumors, underscoring the need to investigate the incidence of brain metastasis among ER-low tumors to better identify high-risk populations and optimize patient selection for future clinical trials. Methods: A retrospective cohort study was performed using the 2022 NCDB Participant User File. We collected patients with de novo stage IV breast cancer from 2018-2022, as 2018 was the first year that ER was defined as a continuous variable allowing categorization of ER. ER status was categorized as ER <1% (negative), 1-10% (low), and >10% (positive). Demographic, clinicopathologic, and treatment variables were compared across ER groups using chi-square or Fisher's exact tests for categorical variables and t-test or Kruskal-Wallis tests for continuous variables. Associations between ER status and brain metastases (BrM) at diagnosis (yes vs no) were evaluated using univariate logistic regression. Overall survival (OS) was assessed using cox proportional hazards model for patients who had BrM. Results: A total of 18,783 patients were included in the analysis. Most were aged 60-69 years (30.5%), 77.0% were White, 85.0% had infiltrating ductal carcinoma, and 51.7% had grade 3 histology. ER status was negative in 23.0%, low in 3.1%, and positive in 73.9%. HER2 status was negative in 70.2%, low in 10.7%, positive in 14.5%, and unknown in 4.6%. Overall, 7.3% of patients had BrM at baseline. BrM were higher in ER-negative (12.0%) and ER-low (10.0%) tumors vs ER-positive disease (5.7%) [Odds ratio: ER-negative; 2.24 (95% CI: 2-2.52), ER-low; 1.82 (95%CI: 1.38-2.41) compared to ER-positive] in univariate logistic regression. OS among patients with BrM was similar between groups (ER-negative; HR 0.93 [0.71-1.22], ER-low; HR 0.91 [0.43-1.93] compared to ER-positive). Conclusions: The proportion of BrM at diagnosis in ER-low breast cancer was more similar to ER-negative than ER-positive disease. However, the OS in patients with brain metastasis was similarly poor across all ER subtypes, suggesting that once brain involvement occurs, underlying histology has limited prognostic impact. These findings highlight the similar clinical features of ER-low and ER-negative disease, reinforce prompt evaluation of neurologic symptoms, and encourage greater inclusion of this subgroup in BrM-specific clinical trials.