Increased regulatory T-cell numbers distinguish high-risk breast cancer patients and those at risk of late relapse

Background

We aimed to assess the clinical significance of tumour-infiltrating FOXP3+ regulatory T cells (T_R) in breast cancer patients with long-term follow-up.

Methods

FOXP3+ T_R were detected by immunohistochemistry with our new FOXP3 monoclonal antibody, 236A/E7. Numbers of FOXP3+ lymphocytes in tissue microarray cores from pure ductal carcinoma in situ (DCIS) (n = 62), from invasive breast cancer (n = 237) or from comparable areas of normal terminal duct lobular breast tissue from patients without cancer (n = 10) were determined. A median cutoff value of 15 defined patients with high numbers of T_R.

Results

T_R numbers were significantly higher in DCIS and invasive breast carcinomas when compared with normal breast, with invasive tumours having significantly higher numbers than DCIS (P = 0.001). High numbers of FOXP3+ T_R identified patients with DCIS at increased risk of relapse (P = 0.04) and patients with invasive tumours having both shorter relapse-free (P = 0.004) and overall survival (P = 0.007). High T_R numbers were present in high-grade tumours (P < 0.001), in patients with lymph node involvement (P = 0.01) and in estrogen receptor alpha (ER)-negative tumours (P = 0.001). Importantly, quantification of FOXP3+ T_R identified a group at high risk of relapse, within the so-called good prognostic group of ER-positive patients (P = 0.005) and these patients have a prognosis as poor as those that lack ER expression. Multivariate analyses, in ER-positive patients, demonstrated that greater T_R numbers independently conferred a significantly higher hazard ratio than that of tumour grade and nodal status for relapse-free and overall survival, respectively. Unlike conventional clinicopathological factors, high numbers of FOXP3+ T_R identified patients at risk of late relapse after 5 years disease-free survival.

Conclusion

These findings indicate that quantification of FOXP3+ T_R in breast tumours is valuable for assessing disease prognosis and progression, and represents a novel marker for identifying late-relapse patients who may benefit from aromatase therapy after 5 years of tamoxifen treatment. Furthermore, tumour vaccination approaches in combination with targeting T_R cells are just entering clinical trials and our data strongly suggest that such therapy would be beneficial for a significant proportion of breast cancer patients.