The Value of Tumor Infiltrating Lymphocytes (TILs) for Predicting Response to Neoadjuvant Chemotherapy in Breast Cancer: A Systematic Review and Meta-Analysis

Abstract

BackgroundWe carried out a systematic review and meta-analysis to evaluate the predictive roles of tumor infiltrating lymphocytes (TILs) in response to neoadjuvant chemotherapy (NAC) in breast cancer.MethodA PubMed and Web of Science literature search was designed. Random or fixed effect models were adopted to estimate the summary odds ratio (OR). Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. Publication bias was evaluated using a funnel plot, Egger's test and Begg's test. We included studies where the predictive significance of TILs, and/or TILs subset on the pathologic complete response (pCR) were determined in NAC of breast cancer.ResultsA total of 13 published studies (including 3251 patients) were eligible. In pooled analysis, the detection of higher TILs numbers in pre-treatment biopsy was correlated with better pCR to NAC (OR = 3.93, 95% CI, 3.26–4.73). Moreover, TILs predicted higher pCR rates in triple negative (OR = 2.49, 95% CI: 1.61–3.83), HER2 positive (OR = 5.05, 95% CI: 2.86–8.92) breast cancer, but not in estrogen receptor (ER) positive (OR = 6.21, 95%CI: 0.86–45.15) patients. In multivariate analysis, TILs were still an independent marker for high pCR rate (OR = 1.41, 95% CI: 1.19–1.66). For TILs subset, higher levels of CD8+ and FOXP3+ T-lymphocytes in pre-treatment biopsy respectively predicted better pathological response to NAC (OR = 6.44, 95% CI: 2.52–16.46; OR = 2.94, 95% CI: 1.05–8.26). Only FOXP3+ lymphocytes in post-NAC breast tissue were a predictive marker for low pCR rate in univariate (OR = 0.41, 95% CI: 0.21–0.80) and multivariate (OR = 0.36, 95% CI: 0.13–0.95) analysis.ConclusionHigher TILs levels in pre-treatment biopsy indicated higher pCR rates for NAC. TILs subset played different roles in predicting response to NAC.

Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy

“…The results of the present study revealed that the intratumoral expression of CD8 + TIL may be predictive of pCR in this patient population. Similar to previous studies (17,21,22,(40)(41)(42), 56% of patients with high intratumoral expression of CD8 + TIL achieved a pCR, in contrast with 13.3% for patients with low intratumoral CD8 + TIL. Denkert et al (17) investigated intratumoral and stromal lymphocytes in a total of 1,058 pre-therapeutic BC core biopsies from two neoadjuvant anthracycline/taxane-based studies.…”

“…TILs detected in the pre-treatment biopsy indicated a 2.5 and 5 times increased probability of pCR in patients that were TNBC-and HER 2-positive, respectively. Notably, no reported effects were observed in ER-positive patients (41).…”

“…In addition, West et al (40) demonstrated that higher TIL counts detected by eight-gene expression profiling were correlated with the pCR rate in TNBC-and HER 2-positive tumors. In a previous systematic review and meta-analysis, Mao et al (41) observed that a high number of TILs, either stromal or intra-tumoral or both, is a significant predictor of pCR for patients treated with NC. TILs detected in the pre-treatment biopsy indicated a 2.5 and 5 times increased probability of pCR in patients that were TNBC-and HER 2-positive, respectively.…”

Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer

“…4–6 However, a meta-analysis of 13 studies and 3251 patients suggests that this association is not apparent in hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) BC. 7 Confusingly, an analysis of 3771 samples from patients enrolled in six randomized trials demonstrated that higher TIL counts were associated with decreased overall survival (OS) in HR positive BC, although TILs were associated with a higher probability for pCR in the same patients 6 Moreover, few studies have reported on TIL kinetics under NACT, with the vast majority of those comparing pre-chemotherapy samples with surgical specimens, after the completion of the entire schedule of NACT. Again, the published results are inconsistent, with studies suggesting both improved 8, 9 and worse patient outcomes 10 , 11 associated with high TIL counts after NACT.…”

Immune Blockade Inhibition in Breast Cancer

“…Additional studies in the neo-adjuvant setting were performed and reviewed in a meta-analysis that studied the value of TILs as a predictor of pathologic complete response (pCR) after neo-adjuvant chemotherapy (34). Higher TILs numbers were associated with a better rate of pCR overall and in triple-negative and Her2-positive carcinomas but not in ER-positive cancers.…”