title: 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.
authors.affiliation: Oncology Center of Excellence, International Medical Center, PO Box 2172, Jeddah, 21451, Kingdom of Saudi Arabia, ezzibrahim@imc.med.sa.
authors.forename: Ezzeldin M
authors.initials: EM
authors.lastname: Ibrahim
authors.forename: Meteb E
authors.initials: ME
authors.lastname: Al-Foheidi
authors.forename: Mubarak M
authors.initials: MM
authors.lastname: Al-Mansour
authors.forename: Ghieth A
authors.initials: GA
authors.lastname: Kazkaz
mesh_terms: D014408:Biomarkers, Tumor; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000473:pathology; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors