Significance of Tumor-Infiltrating Lymphocytes and the Expression of Topoisomerase IIα in the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy

Abstract

Purpose: The aim of this study was to determine factors able to predict chemotherapeutic responses and clinical outcomes in patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). Methods: Fifty-two TNBC patients on taxane-anthracycline-based NAC were included. The expression of Ki67, topoisomerase IIα (TOPOIIα), and p53, as well as the presence of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs were evaluated in biopsy specimens by immunohistochemistry. The expression of Ki67, TOPOIIα, and p53, as well as CD4 and CD8 in TILs was calculated according to the pathological response to NAC, disease-free survival (DFS), and overall survival (OS). Results: Fourteen (26.9%) TNBC patients demonstrated a pathological complete response (pCR). According to univariate analyses, significant factors associated with pCR were high infiltration of CD4+ TILs (p = 0.004), high infiltration of CD8+ TILs (p = 0.010), and high expression of topoisomerase IIα (TOPOIIα) (p = 0.006). CD4+ TILs and TOPOIIα were significantly positively correlated with CD8+ TILs. Multivariate analyses indicated that TOPOIIα was an independent predictor of pCR. Although TNBC patients with high infiltration of CD4+ TILs, CD8+ TILs, or with high expression of TOPOIIα exhibited a significantly good 5-year DFS, only TNBC patients with a high infiltration of CD8+ TILs exhibited significantly positive 5-year OS probabilities. Conclusion: Our study demonstrated that CD4+ TILs and TOPOIIα in pretreated cancer tissues were significantly correlated with CD8+ TILs. CD4+ TILs, CD8+ TILs, and TOPOIIα expression were predictors of pCR and 5-year DFS of TNBC patients who were treated with NAC, and TOPOIIα was an independent predictor of pCR. CD8+ TILs were a key factor in the prediction of good 5-year OS rates of TNBC patients after taxane-anthracycline-based NAC.

Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

“…BRCA1-IRIS overexpressing (IRISOE) TNBC carcinomas had more CD25 + /Foxp3 + Tregs and few CD8 + /PD-1 + cytotoxic T-cells, which showed that the interaction between macrophages and IRISOE cells initiated an immunosuppressive TME within TNBC tumors [71]. TOPOIIα and CD4 + TILs were significantly positively associated with CD8 + TILs and they exhibited a significantly good 5-year DFS but only a high infiltration of CD8 + TILs showed significantly better 5-year OS in 52 TNBC patients that received taxane-anthracycline-based NAC [103,104]. Calcium/calmodulin-dependent kinase (CaMKK2), expressed in tumor-related stromal cells, could promote tumor growth.…”

Dual Role of p73 in Cancer Microenvironment and DNA Damage Response

“…The same stimuli that activate p53 are likely to activate p73 as well [ 181 ]. If true, then p73 should induce the T-cell death and attenuate their well-documented antitumour effects in nearly all cancer types [ 182 , 183 , 184 ]. Noteworthy, TNFa-induced T-cell apoptosis was dependent on the p73, but not p53 [ 163 ].…”

Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives

“…This is in line with the rationale for an immunomodulatory function of the immune infiltrate and with the prognostic impact we previously discussed. Furthermore, available data also suggests that higher CD8 + /FOXP3 + ratios and high levels of CD4 + and CD8 + TILs are associated with a greater probability of obtaining pCR in eTNBC ( 88 , 96 ). In addition, the presence of TILs both at presentation and in the residual disease after exposure to systemic treatment is associated with a favorable outcome and seems to be inversely related to the activation of the cell proliferation RAS/MAPK pathway ( 88 ).…”