The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis

Abstract

In a recent meta-analysis, we demonstrated that rich tumor-infiltrating lymphocytes (TILs) were significantly correlated to a favorable breast cancer (BC) outcome largely in estrogen receptor-negative tumors. It is known that TILs predominate in triple-negative (TN) BC, and to the best of our knowledge, there is no published meta-analysis that examined their prognostic value exclusively in that subtype. Therefore, we planned this meta-analysis to explore the clinical utility of rich TILs in TN-BC. According to predefined selection criteria, literature search identified eight eligible studies. The meta-analysis included data on 2,987 patients with early stage BC. The median percentage of lymph node positivity was 47% (95% confidence interval [CI] 23-82%). Over a median follow-up of 113 months (95% CI 80-144 months), it was found that rich TILs were associated with 30% (hazard ratio [HR] = 0.70; 95% CI 0.56-0.87; P = 0.001), 22% (HR = 0.78; 95% CI 0.68-0.90; P = 0.0008), and 34% (HR = 0.66; 95% CI 0.53-0.83; P = 0.0003), reduction in the risk of recurrence, distant recurrence, and death, respectively. In addition, for every 10% increments in rich TILs, there was an approximate 15-20% reduction in any recurrence, distant recurrence, or mortality. Moreover, rich TILs predicted superior overall survival (OS) benefit irrespective of the disease phenotype (TN-BC or core-basal phenotype), TILs location (intratumoral or stromal), or TILs qualification as either TILs-non-specified, cytotoxic (CD8+) or regulatory (forkhead box protein 3, FOXP3+) T cells. Data on 5-negative phenotype population were limited, and rich TILs failed to demonstrate a prognostic significance in this phenotype. To investigate the heterogeneity that was shown in the analyses of disease-free survival and OS, a set of meta-analyses showed that the method used in TILs detection (hematoxylin and eosin stains vs. immunohistochemistry) could explain most of the variability in the pooled estimates. Rich TILs were significantly associated with better survival outcome in early TN-BC and should be considered as a strong prognostic factor in this subtype. The results from the current meta-analysis support integrating immunotherapy with conventional therapy in future BC research.

Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

“…As previously reported in other meta-analyses of randomized and nonrandomized trials, our results suggest that TNBC patients with a particularly strong lymphocytic infiltrate (i.e., LPBC) were more likely to experience pCR compared with patients with low lymphocytic infiltrate [19,24]. In the adjuvant setting, despite the good prognosis of TNBC patients with very high sTILs, these patients should not be spared chemotherapy in light of the recentdata derived from two RCTs comparing adjuvant anthracyclines (which induce immunogenic cell death in preclinical models) versus no adjuvant chemotherapy.…”

CD103 and Intratumoral Immune Response in Breast Cancer

“…The value of evaluating tumor-infiltrating leucocytes (TIL) as a diagnostic, prognostic, and predictive biomarker in breast cancer has now been shown by a range of studies (1)(2)(3)(4)(5). In many of these studies, the evaluation of TIL was based on H&E-stained sections and recommendations around the conduct of this effective and simple "immunoscore" may improve the standardization for clinical implementation (6).…”

Towards tumor immunodiagnostics

“…In accordance to these studies, a meta-analysis including 16,097 patients found that rich in TILs ER− breast carcinomas were associated with favorable prognosis (33). High TILs were associated with response to neoadjuvant chemotherapy (38), in two meta-analyses including 3,251 patients (39) and 12,968 patients (40), in ER− breast carcinomas, according to a meta-analysis with 16,097 patients (33), in HER2+ breast carcinomas and TNBC (41).…”

“…A meta-analysis of TILs in early, TNBCs noted that TIL-rich TNBCs were associated with better OS (HR 0.66, 95% CI: 0.53-0.83) irrespectively of TIL location (intratumoral or stromal) or mode of detection (H&E, CD8+ or Foxp3+ populations) (33).…”