Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis

Abstract

Background: The objective of this systematic review and meta-analysis was to determine the prognostic value of total tumor-infiltrating lymphocytes (TILs) and subtypes of TILs (CD4⁺, CD8⁺, and FOXP3⁺) in triple-negative breast cancer (TNBC).

Methods: A systematic search of the MEDLINE, EMBASE, and Web of Science databases was conducted to identified eligible articles published before August 2019. Study screening, data extraction, and risk of bias assessment were performed by two independent reviewers. Risk of bias on the study level was assessed using the ROBINS I tool and Quality in Prognosis Studies (QUIPS) tool. We performed a meta-analysis to obtain a pooled estimate of the prognostic role of TILs using Review Manager 5.3.

Results: In total, 37 studies were included in the final analysis. Compared to TNBC patients with low TIL levels, TNBC patients with high TIL levels showed a higher rate of pathological complete response (pCR) to treatment (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.43-3.19). With each 10% increase in percentage of TILs, patients with TNBC had an increased pCR (OR 1.09, 95% CI 1.02-1.16). Compared to TNBC patients with low TIL levels, patients with high TIL levels had better overall survival (OS; hazard ratio [HR] 0.58, 95% CI 0.48-0.71) and disease-free survival (DFS; HR 0.66, 95% CI 0.57-0.76). Additionally, with a continuous increase in TIL levels, patients with TNBC had improved OS (HR 0.90, 95% CI 0.87-0.93) and DFS (HR 0.92, 95% CI 0.90-0.95). A high CD4⁺ TIL level was associated with better OS (HR 0.49, 95% CI 0.32-0.76) and DFS (HR 0.54, 95% CI 0.36-0.80). A high CD8⁺ TIL level was associated better DFS only (HR 0.55, 95% CI 0.38-0.81), as no statistical association was found with OS (HR 0.70, 95% CI 0.46-1.06). A high FOXP3⁺ TIL level also was associated with only DFS (HR 0.50, 95% CI 0.33-0.75) and not OS (HR 1.28, 95% CI 0.24-6.88).

Conclusions: TNBC with a high level of TILs showed better short-term and long-term prognoses. High levels of specific phenotypes of TILs (CD4⁺, CD8⁺, and FOXP3⁺) were predictive of a positive long-term prognosis for TNBC.

Keywords: Meta-analysis; Prognosis; Triple-negative breast cancer; Tumor-infiltrating lymphocytes.

Fig. 1

PRISMA flow diagram detailing the search strategy and results [11]

Fig. 2

Forest plots of the random-effects meta-analysis for the efficacy of tumor-infiltrating lymphocytes (TILs) for predicting pathological complete response (pCR). a Low TILs vs. high TILs stratified by TIL phenotype. b Continuous TILs (10% increase) for pCR

Fig. 3

Forest plots of the random-effects meta-analysis for the efficacy of tumor-infiltrating lymphocytes (TILs) for overall survival (OS). a Low TILs vs. high TILs stratified by TIL phenotypes. b TILs stratified by continuous TILs, 5% increase in TILs, 10% increase in TILs, and phenotypes

Fig. 4

Forest plots of the random-effects meta-analysis for the efficacy of tumor-infiltrating lymphocytes (TILs) for disease-free survival (DFS). a Low TILs vs. high TILs stratified by TIL phenotype. b TILs stratified by continuous TILs, 5% increase in TILs, and 10% increase in TILs

Fig. 5

Risk of bias assessment at the study level. a Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included full reported studies (n = 37). b Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

Fig. 6

Funnel plot analysis of potential publication bias. a High tumor-infiltrating lymphocytes (TILs) vs. low TILs for pathological complete response (pCR). b Continuous TILs (10% increase) for pCR. c High TILs vs. low TILs for overall survival (OS). d Continuous TILs for OS. e High TILs vs. low TILs for disease-free survival (DFS). f Continuous TILs for DFS