Prognostic significance of tumor-infiltrating CD8 ⁺ and FOXP3 ⁺ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study

Abstract

Introduction

The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8 ⁺ TILs and FOXP3 ⁺ TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC).

Methods

One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8 ⁺ TIL and FOXP3 ⁺ TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8 ⁺ TIL and FOXP3 ⁺ TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated.

Results

TNBC patients with high CD8 ⁺ TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8 ⁺ TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537–6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029–4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS ( P=0.0064 and P=0.0015, respectively). High CD8 ⁺ TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499–9.581, P=0.0036). Nodal status was also associated with BCSS ( P=0.0024). TNBC with a high rate of CD8 ⁺ TIL changes was associated with significantly better RFS compared with the low group ( P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates ( P=0.011 and P=0.023, respectively).

Conclusions

This is the first study to demonstrate that high CD8 ⁺ TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0632-x) contains supplementary material, which is available to authorized users.