Prognostic Impact of ER-Staining Patterns and Heterogeneity of ER positive HER2 negative Breast Cancer

Background Estrogen receptor (ER) expression is critical in breast cancer treatment. While low ER (1%-9%) resembles triple-negative cancer with chemotherapy efficacy, the significance of “intermediate expression” (≥ 10%) and the therapeutic efficacy remain unclear. This study explores differences in staining patterns and molecular characteristics of ER-low to intermediate expression to guide treatment. Methods A total of 104 breast cancer patients treated between January 2008 and July 2024 with an Allred Proportion Score (PS) of 2 to 4 were included. PS2 (n = 21) was classified as ER-low, while PS3 (n = 26) and PS4 (n = 57) as ER-intermediate (ER-int). ER-int was further divided by ER staining pattern: “Island” (heterogeneous) and “Scatter,” (uniform) subgroups. Prognosis, clinical factors, and gene expression profiles (n = 11) were analyzed. Results The Island subgroup was associated with poorest prognosis ( p  = 0.0116), particularly among patients treated with endocrine-only treatment patients ( p  < 0.0001). Elevated tumor-infiltrating lymphocyte (TIL) levels correlated with worse prognosis in endocrine-only treatment patients ( p  < 0.0043), with TIL levels highest in ER-low, followed by Island and Scatter subgroups. Island tumors were enriched in CD36, GZMB, and type I interferon genes; additionally, 23 “ISLAND” genes showed significant prognostic differences in the TCGA BRCA ER-int (10–69%) cohort. Conclusion This study emphasizes the importance of recognizing heterogeneity within the ER-int subtype. Identifying distinct ER staining patterns and prognostic significance of TILs and transcriptome in ER-int tumors suggests the need for individualized treatment strategies for Island subtype.