Breast tumors with intermediate ER expression differ biologically from ER-low tumors and exhibit a more favorable prognosis.

Background: Estrogen receptor (ER) expression in breast cancer exhibits a widely recognized bimodal distribution, with increasing focus on the biological and clinical characteristics of the low-expression group. However, tumors with intermediate ER expression have been relatively understudied. This study aimed to clarify the clinicopathological and prognostic features of ER-intermediate (ER-int) tumors by comparing them with ER-low tumors.

Methods: Tumors were classified into ER-low (1-10%), ER-int (11-70%), and ER-high (71-100%) groups based on immunohistochemistry. We retrospectively analyzed 261 breast cancer patients with ER-low or ER-int tumors who underwent curative surgery. Clinicopathological features and treatment outcomes were compared, and factors influencing distant recurrence-free survival (DRFS) and overall survival (OS) were evaluated using Cox proportional hazard models. For analysis of clinical outcomes, after excluding HER2-positive tumors, an additional cohort of 604 patients with ER-high and HER2-negative tumors was also compared.

Results: ER-int tumors showed lower nuclear grade, higher progesterone receptor expression, and lower Ki67 labeling index compared with ER-low tumors. Pathological stage was independently associated with both DRFS and OS. In addition, ER status was also an independent factor for OS, with ER-int tumors showing significantly better OS than ER-low tumors (P = 0.014).

Conclusions: Our findings, based on comparison with ER-low tumors, suggest that intermediate ER expression may represent a biologically and clinically heterogeneous subgroup within ER-positive breast cancers. Recognition of this heterogeneity could help refine classification and support more individualized treatment strategies.