Association between levels of tumor-infiltrating lymphocytes in different subtypes of primary breast tumors and prognostic outcomes: a meta-analysis

Abstract

Background To investigate the impact of the elevation of tumor-infiltrating lymphocytes (TILs) in different molecular subtypes of primary breast cancer, i.e. each 10% increment of TILs and high-level TILs (TILs≥50%) in tumor, on overall survival (OS) and pathological complete response (pCR) and to compare the presentation of high-level TILs across these molecular subtypes. Methods Citation retrieval was performed in the PubMed, Cochrane Library, Embase and Web of Science databases. All statistical calculations were performed by the software of StataSE version 12.0. Results Twenty-two eligible clinical trials including 15,676 unique patients were included for meta-analysis. Each 10% increment of TILs significantly improved OS in human epidermal growth factor receptor 2 (HER2)-overexpression (pooled Hazard ratio (HR), 0.92; 95% CI, 0.89–0.95) and triple-negative (TN) (pooled HR, 0.90; 95% CI, 0.89–0.92) breast tumors but not in luminal tumor subtype (pooled HR, 1.06; 95% CI, 0.99–1.13). It was also associated with an increased pCR rate in breast cancers (pooled Odds ratio (OR), 1.27; 95% CI, 1.19–13.5). High-level TILs were significantly related with a higher pCR rate (pooled OR, 2.73; 95% CI, 2.40–3.01) than low-level TILs. The HER2-amplified (pooled OR, 3.14; 95% CI, 1.95–5.06) and TN (pooled OR, 4.09; 95% CI, 2.71–6.19) phenotypes of breast cancers expressed significantly more high-level TILs than the luminal tumor subtype, although the presentation of those between the former two subsets was not significantly different (pooled OR, 1.30; 95%CI, 0.83–2.04). Conclusions The elevation of TILs in breast tumors predicts favorable prognostic outcomes, particularly in the HER2-overexpression and TN subtypes.

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

“…The achievement of pathological complete response (pCR) is a favorable prognostic factor for human epidermal growth factor receptor 2 (HER-2)-positive, triple-negative (TN), and high-grade hormone receptor (HR)-positive HER-2-negative breast cancers [ 10 ]. The presence and abundance of tumor-infiltrating lymphocytes (TILs) before NAC play crucial roles in the induction of therapeutic effects and favorable prognostic outcomes after chemotherapy for HER-2-positive and TN breast cancers [ 11 ]. After NAC, the activation of antitumor immunity through innate and adaptive immune responses, such as natural killer (NK) and CD8+ T cell activity, and the downregulation of immunosuppressive factors such as regulatory T cells (Tregs) and cytotoxic T lymphocyte antigen 4 within them, are important for the enhancement of the therapeutic effect [ 12 , 13 ].…”

Biomarkers and potential targets for immune and cellular therapy in triple negative breast cancer

“…The results of multivariate analysis showed that any 10% increase in TIL density was associated with increase in overall survival and complete morphological response rates for all molecular subtypes. High TIL density (≥50%) leads to a 2.7fold increase in the complete response rates in TNB [54].…”

Therapeutic Associations Comprising Anti-PD-1/PD-L1 in Breast Cancer: Clinical Challenges and Perspectives

“…However, this prognostic and predictive impact of the efficacy of chemotherapy depends on the breast cancer subtype, and is particularly marked in the triple negative and HER2 positive subtypes, in which there is more often a higher TMB, as well as greater inflammatory signature expression. Moreover, in the HER2 positive subtype, the immune response (in particular TIL levels) also seems to influence the effectiveness of anti-HER2 treatments, in particular monoclonal antibodies (possibly by the phenomenon of Antibody-Dependent Cell Cytotoxicity (ADCC)) [ 7 , 9 , 10 , 11 ]. Among TILs, the presence of CD8 + T cells, as well as the ratio between effector CD8 + and regulatory FoxP3 + T cells, appears to be associated with both better prognosis and long-term survival [ 7 , 12 , 13 ].…”