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Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse

Gaynor J. Bates, Stephen B. Fox, Cheng Han, Russell D. Leek, José F. Garcia, Adrian L. Harris, Alison H. Banham

From the Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital; Cancer Research UK Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; and Monoclonal Antibodies Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Address reprint requests to Gaynor J. Bates, PhD, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, United Kingdom; e-mail: gaynor.bates{at}ndcls.ox.ac.uk

PURPOSE: To assess the clinical significance of tumor-infiltrating FOXP3-positive regulatory T cells (T_R) in breast cancer patients with long-term follow-up.

PATIENTS AND METHODS: FOXP3-positive T_R were detected by immunohistochemistry with our new, extensively characterized FOXP3 monoclonal antibody, 236A/E7. Numbers of FOXP3-positive lymphocytes in tissue microarray cores from pure ductal carcinoma in situ (DCIS; n = 62), invasive breast cancer (n = 237) or from comparable areas of normal terminal duct lobular breast tissue (n = 10) were determined. A median cutoff of 15 defined patients with high numbers of T_R.

RESULTS: T_R numbers were significantly higher in in situ and invasive breast carcinomas than in normal breast; invasive tumors have significantly higher numbers than DCIS (P = .001). High numbers of FOXP3-positive T_R identified patients with DCIS at increased risk of relapse (P = .04) and patients with invasive tumors with both shorter relapse-free (P = .004) and overall survival (P = .007). High T_R numbers were present in high-grade tumors (P .001), in patients with lymph node involvement (P = .01), and in estrogen receptor (ER) –negative tumors (P = .001). Importantly, high numbers of T_R within ER-positive tumors identified high-risk patients (P = .005). Unlike conventional clinicopathologic factors, high numbers of FOXP3-positive T_R can identify patients at risk of relapse after 5 years.

CONCLUSION: These findings indicate that quantification of FOXP3-positive T_R in breast tumors is valuable for assessing disease prognosis and progression, and that T_R are an important therapeutic target for breast cancer. FOXP3-positive T_R represent a novel marker for identifying late-relapse patients who may benefit from aromatase therapy after standard tamoxifen treatment.

Supported by Breast Cancer Campaign, Cancer Research UK and Leukaemia Research Fund.

Presented in part at the 21st Genes and Cancer Meeting, December 13-15, 2004, University of Warwick, United Kingdom; and at the 5th European Breast Cancer Conference, March 21-25, 2006, Nice, France.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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