Expression patterns and prognostic implications of tumor-infiltrating lymphocytes dynamics in early breast cancer patients receiving neoadjuvant therapy: A systematic review and meta-analysis

Abstract

PurposeHigh levels of tumor-infiltrating lymphocytes (TILs) are associated with better outcomes in early breast cancer and higher pathological response rates to neoadjuvant chemotherapy especially in the triple-negative (TNBC) and HER2+ subtypes. However, the dynamic changes in TILs levels after neoadjuvant treatment (NAT) are less studied. This systematic review and meta-analysis aimed to investigate the patterns and role of TILs dynamics change in early breast cancer patients receiving NAT.MethodsMedline, Embase, Web of Science Core Collection and PubMed Central databases were searched for eligible studies. Data were extracted independently by two researchers and discordances were resolved by a third. Pooled TILs rates pre- & post-treatment (overall and per subtype), pooled rates of ΔTILs and direction of change after NAT as well as correlation of ΔTILs with survival outcomes were generated in the outcome analysis.ResultsOf 2116 identified entries, 34 studies fulfilled the criteria and provided adequate data for the outcomes of interest. A decreased level of TILs was observed after NAT in paired samples across all subtypes. The effect of NAT on TILs was most prominent in TNBC subtype with a substantial change, either increase or decrease, in 79.3% (95% CI 61.7-92.6%) of the patients as well as in HER2+ disease (14.4% increased vs 46.2% decreased). An increase in ΔTILs in TNBC was associated with better disease-free/relapse-free survival in pooled analysis (univariate HR = 0.59, 95% CI: 0.37–0.95, p = 0.03).ConclusionThis meta-analysis illustrates the TILs dynamics during NAT for breast cancer and indicates prognostic implications of ΔTILs in TNBC. The potential clinical utility of the longitudinal assessment of TILs during neoadjuvant therapy warrants further validation.

Effect of Neoadjuvant Chemotherapy on Tumor-Infiltrating Lymphocytes in Resectable Gastric Cancer: Analysis from a Western Academic Center

“…This may have been a consequence of a generalized influx of immune cells after NAC and/or the body's attempt to attenuate a heightened pro-inflammatory, anti-tumor response. Notably, we also observed an improved pathologic response to preoperative chemotherapy in a select subset of patients with the highest quartile of intratumoral-and stromal-infiltrating immune cells, supporting previous work demonstrating similar results in other NAC-treated carcinomas [46][47][48]. Nevertheless, given that distant metastases are the primary mode of failure for gastric cancer, there are evidently a multitude of mechanisms driving tumor immune evasion and progression that may be independent of the TILs that are associated with the primary tumor [49].…”

Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade

“…Our findings that ERBB2 gene expression is strongly associated with pCR, but expression of immune genes is not, may be supportive of this idea. However, another explanation would be that TILs and immune gene expression in pretreatment biopsies may not be suitable predictors of potential immune activation, as it has been shown that the immune infiltrate is dynamic and changes during treatment are associated with outcome 38 . Studies evaluating TILs in on-treatment biopsies and in residual disease of patients with no https://doi.org/10.1038/s41523-024-00636-4 pCR, may help to better understand this dynamic state in HER2-positive disease.…”

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

“…An increase in TILs during neoadjuvant treatment appears to be associated with better outcomes in TNBC. The survival benefit of higher levels of infiltration was demonstrated in a meta-analysis that analyzed studies that performed paired analyses of TILs density before and after NACT ( 75 ). The NeoTRIP study also demonstrated an increase in TILs after 1 cycle of neoadjuvant systemic therapy ( 76 ).…”