Prognostic significance of FOXP3+tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration

Introduction: 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. Methods: 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). Results: 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. Conclusions: 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.