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. 2014 Sep 6;16(5):432.
doi: 10.1186/s13058-014-0432-8.

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

Shuzhen Liu, William D Foulkes, Samuel Leung, Dongxia Gao, Sherman Lau, Zuzana Kos, Torsten O Nielsen

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

Shuzhen Liu et al. Breast Cancer Res. .

Abstract

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.

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Figures

Figure 1
Figure 1
Breast cancer-specific survival (BCSS) stratified by FOXP3+ iTILs in ER-positive and ER-negative breast cancers. (a) ER+, (b) ER–. ER, estrogen receptor; iTILs, intratumoral tumor-infiltrating lymphocytes.
Figure 2
Figure 2
Breast cancer-specific survival (BCSS) stratified by FOXP3+ iTILs in different subtypes of ER– breast cancer. (a) HER2+/ER–, (b) core basal, and (c) five-marker negative phenotype (5NP) subgroup. ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; iTILs, intratumoral tumor-infiltrating lymphocytes.
Figure 3
Figure 3
Breast cancer-specific survival (BCSS) by FOXP3+ iTILs in HER2+/ER– and core basal intrinsic subtypes, stratified by CD8+ iTILs status. (a) HER2+/ER– with no CD8+ iTILs, (b) HER2+/ER– with presence of CD8+ iTILs, (c) core basal with no CD8+ iTILs, and (d) core basal with presence of CD8+ iTILs. ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; iTILs, intratumoral tumor-infiltrating lymphocytes.
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