Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

Carbognin, Luisa; Pilotto, Sara; Nortilli, Rolando; Brunelli, Matteo; Nottegar, Alessia; Sperduti, Isabella; Giannarelli, Diana; Bria, Emilio; Tortora, Giampaolo

doi:10.1634/theoncologist.2015-0307

Cited by 50 publications

(38 citation statements)

References 53 publications

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“…Additionally, with a continuously increasing TIL levels, patients with TNBC had improved OS (HR 0.90, 95% CI 0.87-0.93) and DFS (HR 0.92, 95% CI 0.90-0.95). This finding is consistent with previous conclusions [3,9,25,58,59]. Our results indicate that a high level of TILs is a positive predictor for the prognosis of patients with TNBC.…”

Section: Discussionsupporting

confidence: 94%

Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis

et al. 2020

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Background: The objective of this systematic review and meta-analysis was to determine the prognostic value of total tumor-infiltrating lymphocytes (TILs) and subtypes of TILs (CD4 + , CD8 + , and FOXP3 + ) in triple-negative breast cancer (TNBC). Methods:A systematic search of the MEDLINE, EMBASE, and Web of Science databases was conducted to identified eligible articles published before August 2019. Study screening, data extraction, and risk of bias assessment were performed by two independent reviewers. Risk of bias on the study level was assessed using the ROBINS I tool and Quality in Prognosis Studies (QUIPS) tool. We performed a meta-analysis to obtain a pooled estimate of the prognostic role of TILs using Review Manager 5.3. Results:In total, 37 studies were included in the final analysis. Compared to TNBC patients with low TIL levels, TNBC patients with high TIL levels showed a higher rate of pathological complete response (pCR) to treatment (odds ratio [OR] 2.14, 95% confidence interval [CI] 1. 43-3.19). With each 10% increase in percentage of TILs, patients with TNBC had an increased pCR (OR 1.09, 95% CI 1.02-1.16). Compared to TNBC patients with low TIL levels, patients with high TIL levels had better overall survival (OS; hazard ratio [HR] 0.58, 95% CI 0.48-0.71) and diseasefree survival (DFS; HR 0.66, 95% CI 0.57-0.76). Additionally, with a continuous increase in TIL levels, patients with TNBC had improved OS (HR 0.90, 95% CI 0.87-0.93) and DFS (HR 0.92, 95% CI 0.90-0.95). A high CD4 + TIL level was associated with better OS (HR 0.49, 95% CI 0.32-0.76) and DFS (HR 0.54, 95% CI 0.36-0.80). A high CD8 + TIL level was associated better DFS only (HR 0.55, 95% CI 0.38-0.81), as no statistical association was found with OS (HR 0.70, 95% CI 0.46-1.06). A high FOXP3 + TIL level also was associated with only DFS (HR 0.50, 95% CI 0.33-0.75) and not OS (HR 1.28, 95% CI 0.24-6.88). Conclusions: TNBC with a high level of TILs showed better short-term and long-term prognoses. High levels of specific phenotypes of TILs (CD4 + , CD8 + , and FOXP3 + ) were predictive of a positive long-term prognosis for TNBC.

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Section: Discussionsupporting

confidence: 94%

Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis

et al. 2020

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“…TILs in breast cancer is a robust predictive and prognostic marker [28] and their existence in breast cancer tissue before chemotherapy seems to be a good prognostic feature promoting a therapeutic effect of neoadjuvant treatment [29, 30]. …”

Section: Introductionmentioning

confidence: 99%

Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors

et al. 2017

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PurposeTesticular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs.ResultsPD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 – 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 – 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs.Materials and MethodsSurgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method.ConclusionsThe prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.

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“…21 Presence of TILs has been clearly associated with favorable outcome and response to therapy. [13][14][15] In this line, our study also identifies patients with good prognosis. Unfortunately, the available datasets do not provide information to compare our gene signature with the presence of TILs and, therefore, future prospective studies will be necessary.…”

Section: Discussionmentioning

confidence: 60%

“…10 In addition, administration of some therapies including chemotherapy can indirectly activate the immune system by increasing the genomic instability and by releasing tumor neoantigens. [11][12][13] In this context, those tumors that express a higher level of tumor-infiltrating lymphocytes (TILs) respond better to chemotherapy and are associated with favorable outcome. [14][15][16] In our study, we aimed to explore the presence and prognostic role of MHC-I in breast tumors and their association with mutational tumor burden and prognosis.…”

Section: Introductionmentioning

confidence: 99%

Expression of MHC class I, HLA-A and HLA-B identifies immune-activated breast tumors with favorable outcome

et al. 2019

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Antigen recognition by MHC class I molecules is a key step for the initiation of the immune response. We hypothesized that expression of these molecules could be a marker of immune-activated breast cancers. Data from KM Plotter were extracted to develop an exploratory cohort. Information from Cancer Genome Atlas (TCGA) and METABRIC was used to create two validation cohorts. Raw data were reprocessed and analyzed using plyr R and Bioconductor. We predicted epitope-HLA binding to MHC I molecules by using NetMHC 4.0. Cox proportional hazards regression was computed to correlate gene expression and survival outcome. There was a weak but positive correlation between mutational burden and the expression of most MHC class I molecules. In the exploratory cohort, expression of HLA-A and HLA-B was associated with favorable relapse-free survival (RFS) and overall survival (OS) in the basal-like subgroup. This was confirmed in the METABRIC and TCGA dataset. Expression of HLA-A and HLA-B was associated with biomarkers of T cell activation (GZMA, GZMB, and PRF1) and improved the predictive capacity of known immunologic signatures. Several neopeptides expressed in breast cancer were also identified including FUK, SNAPC3, GC, ANO8, DOT1L, HIST1H3F, MYBPH, STX2, FRMD6, CPSF1, or SMTN, among others. Expression of HLA A and B is associated with T cell activation and identifies immune activated, basal-like breast cancers with favorable prognosis. Antigen recognition markers should be incorporated into the assessment of the tumor immune state of basal-like breast patients.

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Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting

Cited by 50 publications

References 53 publications

Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis

Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis

Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors

Expression of MHC class I, HLA-A and HLA-B identifies immune-activated breast tumors with favorable outcome

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