The infiltration of FOXP3⁺ regulatory T cells into invasive tumors has been reported to be associated with survival in a variety of cancers. The prognostic significance of FOXP3⁺ tumor-infiltrating lymphocytes (TILs) in breast cancer, however, remains controversial.

FOXP3⁺ TILs were assessed by immunohistochemistry on tissue microarrays constructed from a well-defined cohort of 3,992 breast cancer patients linked to detailed demographic, biomarker, treatment and outcome data. Survival analyses were performed using the Kaplan-Meier function and Cox proportional hazards regression models to evaluate the association of FOXP3⁺ TILs with breast cancer-specific survival, stratified by intrinsic subtype and cytotoxic T-cell infiltration status (as defined by CD8 immunohistochemistry).

The presence of high numbers of FOXP3⁺ TILs was significantly associated with young age, high grade, estrogen receptor (ER) negativity, concurrent CD8⁺ cytotoxic T-cell infiltration, and human epidermal growth factor receptor-2 positive (HER2⁺)/ER⁺ and core basal subtypes. On multivariate survival analysis, a high level of FOXP3⁺ TILs was significantly associated with poor survival in ER⁺ breast cancers that lacked CD8⁺ T-cell infiltrates (hazard ratio (HR) = 1.30, 95% confidence interval (CI) = 1.02 to 1.66). However, in ER⁺ breast cancers, FOXP3⁺ TILs were strongly associated with improved survival in the HER2⁺/ER⁺ subgroup, particularly in those with co-existent CD8⁺ T-cell infiltrates (HR = 0.48, 95% CI = 0.23 to 0.98), for which the presence of high levels of FOXP3⁺ TILs was independent of standard clinical prognostic factors.

FOXP3⁺ regulatory TILs are a poor prognostic indicator in ER⁺ breast cancer, but a favorable prognostic factor in the HER2⁺/ER⁺ subtype. The prognostic value of FOXP3⁺ TILs in breast cancer differs depending on ER and HER2 expression status and CD8⁺ T-cell infiltration.