Forest plots from the fixed-effect meta-analysis of the efficacy of TILs on the NAC response stratified by different subtypes.

<p>The width of horizontal line represents 95% CI of the individual studies, and the grey boxes represent the weight of each study. The diamond represents the overall summary estimate. The unbroken vertical line was set at the null value (HR = 1.0). Abbreviations: TNBC, triple negative breast cancer; HER2, human epithelial growth factor receptor 2; ER, estrogen receptor.</p

Flow chart of the studies included in the meta-analysis.

<p>Flow chart of the studies included in the meta-analysis.</p

Forest plots of the random/fixed-effects meta-analysis for the efficacy of tumor-infiltrating lymphoctes for disease-free survival (DFS)(A) and overall survival (OS)(B) stratified by infiltration locations, including intratumoral site, stromal site, and both sites in breast cancer (BC) patients.

<p>The horizontal bars indicate the 95% confidence inervals (CIs)The size of the square around eacheffect estimate indicates the weight of the individual study in the meta-analysis.</p

Funnel plot for publication bias in the pooled pCR analysis based on TIL status (A) and TILs subset before (B) treatment.

<p>Funnel plot for publication bias in the pooled pCR analysis based on TIL status (A) and TILs subset before (B) treatment.</p

Forest plots from the random-effect meta-analysis of the efficacy of TILs on the NAC response stratified by infiltration locations in multivariate way.

<p>The width of horizontal line represents 95% CI of the individual studies, and the grey boxes represent the weight of each study. The diamond represents the overall summary estimate. The unbroken vertical line was set at the null value (HR = 1.0).</p

Forest plots from the random-effect meta-analysis of the efficacy of TIL subset on NAC response in pre-treatment biopsy in multivariate way.

<p>The width of horizontal line represents 95% CI of the individual studies, and the grey boxes represent the weight of each study. The diamond represents the overall summary estimate. The unbroken vertical line was set at the null value (HR = 1.0).</p

Baseline Characteristics of Included Studies.

<p>Abbreviations: pts, patients; IHC, immunohistochemistry; HE, staining Hematoxylin-eosin staining; FOXP3, regulatory T-lymphocytes expressing forkhead box P 3 protein; NAC, neoadjuvant chemotherapy; CEF, cyclophosphamide/epirubicin/fluorouracil; CEX, epirubicin/cyclophosphamide/capecitabine; DC, docetaxel/carboplatin; EC, epirubicin/cyclophosphamide; EC-T, epirubicin/cyclophosphamide-taxane; CEF-T, cyclophosphamide/epirubicin/fluorouracil-taxane;T AC, docetaxel/doxorubicin/cyclophosphamide; NX, vinorelbine/capecitabine; TET, docetaxel-docetaxel/epirubicin; AC, doxorubicin/cyclophosphamide; AC-T, doxorubicin/cyclophosphamide-taxane; AD, doxorubicin/docetaxel; AT, doxorubicin/taxane; EC-TX, epirubicin/cyclophosphamide-docetaxel/capecitabine; EC-T-X, epirubicin/cyclophosphamide-docetaxel-capecitabine; PM, paclitaxle/non-pegylated liposomal doxorubicin; PMCb, paclitaxle/non-pegylated liposomal doxorubicin/carboplatin; H, trastuzumab; Bev, bevacizumab; L, lapatinib; EVE, everolimus; IS =  Intratumoral sites; SS =  stromal sites;BS, both sites;10% INC, 10 incr<b>em</b>ent</p><p>a, GeparDuo.</p><p><b>b</b>, GeparTrio.</p><p>Baseline Characteristics of Included Studies.</p

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

<div><p>Background</p><p>We 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.</p><p>Method</p><p>A 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.</p><p>Results</p><p>A 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.</p><p>Conclusion</p><p>Higher TILs levels in pre-treatment biopsy indicated higher pCR rates for NAC. TILs subset played different roles in predicting response to NAC.</p></div

Forest plots from the fixed-effect meta-analysis of the efficacy of TILs on the NAC response stratified by infiltration locations (A) and different cutoff values (B).

<p>The width of horizontal line represents 95% CI of the individual studies, and the grey boxes represent the weight of each study. The diamond represents the overall summary estimate. The unbroken vertical line was set at the null value (HR = 1.0). Abbreviations: LPBC, lymphocyte-predominant breast cancer; TILs, tumor infiltrating lymphocytes.</p

Sensitivity analysis of TILs and TILs subset.

<p>Sensitivity analysis of TILs and TILs subset.</p