Abstract and Introduction
Abstract
Background: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
Patients and methods: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.
Results: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37−0.79] versus CD8−negative tumours (HR = 0.87; 95% CI 0.55–1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (Pheterogeneity = 0.04) and approached significance in imputed data (Pheterogeneity = 0.1).
Conclusions: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/25/8/1536/suppl/DC1] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes.
Introduction
The importance of lymphocytic infiltration in predicting disease progression has been shown in different types of solid tumour but most impressively in colorectal and ovarian cancer where the presence of tumour-infiltrating T cells is associated with reduced recurrence rates and longer survival. Moreover, modulation of the T-cell response has shown clinical efficacy in solid tumours and the tumouricidal effect of trastuzumab has been shown to depend upon the immune response in breast cancer. As a major component of the adaptive immune system, cytotoxic (CD8+) T cells represent a candidate biomarker of the tumour-associated immune response. Most previous studies of CD8+ T lymphocytes in breast cancer have reported an association with favourable outcome but others have not. Unlike CD8+ T lymphocytes, T-regulatory lymphocytes (T-regs) exert an immunosuppressive effect by diminishing the response to self-antigens. Therefore, tumours may hijack this function of T-regs to create an immune-privileged niche to facilitate unimpeded tumour growth. Nuclear expression of forkhead box protein 3 (FOXP3) characterises T-regs. The presence of FOXP3+ T lymphocytes in breast tumours has been associated with both reduced survival and improved survival. In addition to their association with survival, some reports have also found a link between the presence of immune cells and the effect of chemotherapy.
We have investigated the importance of cytotoxic (CD8+) and regulatory (FOXP3+) T cells in breast tumours by conducting a study of over 12 000 patients from the UK and Canada. Our aims were to characterise the effect of these subsets of T lymphocytes on survival, to determine whether this effect is modified by the molecular subtype of the primary tumour and to establish whether lymphocytic infiltration influenced the effect of chemotherapy on breast cancer mortality.