Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes

PURPOSE Tumor-infiltrating lymphocytes (TILs) and their spatial characterizations on whole-slide images (WSIs) of histopathology sections have become crucial in diagnosis, prognosis, and treatment response prediction for different cancers. However, fully automatic assessment of TILs on WSIs currently remains a great challenge because of the heterogeneity and large size of WSIs. We present an automatic pipeline based on a cascade-training U-net to generate high-resolution TIL maps on WSIs. METHODS We present global cell-level TIL maps and 43 quantitative TIL spatial image features for 1,000 WSIs of The Cancer Genome Atlas patients with breast cancer. For more specific analysis, all the patients were divided into three subtypes, namely, estrogen receptor (ER)–positive, ER-negative, and triple-negative groups. The associations between TIL scores and gene expression and somatic mutation were examined separately in three breast cancer subtypes. Both univariate and multivariate survival analyses were performed on 43 TIL image features to examine the prognostic value of TIL spatial patterns in different breast cancer subtypes. RESULTS The TIL score was in strong association with immune response pathway and genes (eg, programmed death-1 and CLTA4). Different breast cancer subtypes showed TIL score in association with mutations from different genes suggesting that different genetic alterations may lead to similar phenotypes. Spatial TIL features that represent density and distribution of TIL clusters were important indicators of the patient outcomes. CONCLUSION Our pipeline can facilitate computational pathology-based discovery in cancer immunology and research on immunotherapy. Our analysis results are available for the research community to generate new hypotheses and insights on breast cancer immunology and development.

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Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer (literature review)

Practical oncology ◽

10.22141/2663-3272.4.1.2021.229870 ◽

2021 ◽

Vol 4 (1) ◽

pp. 39-44

Author(s):

M.O. Bilych

Keyword(s):

Breast Cancer ◽

Predictive Factor ◽

Predictive Value ◽

Tumor Infiltrating Lymphocytes ◽

Breast Cancer Subtypes ◽

Cancer Type ◽

Primary Tumors ◽

Positive Correlation ◽

Cancer Subtypes ◽

Infiltrating Lymphocytes

Background. Breast cancer is the leading cancer type in women. Improvement in its management requires a continuous investigation of new tools for diagnosis and treatment. Biomarkers for breast cancer remain a field of great interest, despite existing knowledge. Extensive research recognizes the critical role played by tumor-infiltrating lymphocytes (TILs) in terms of prognosis and prediction, but much uncertainty still exists about the application of this biomarker in clinical practice. Thus, the purpose of this paper is to review recent researches about the role of TILs as a prognostic and predictive factor in the clinical management of breast cancer subtypes. Materials and methods. Eligible studies from Medline, Pubmed, Google Scholar (2010–2020) databases were analyzed and retrieved. Results. For primary tumors, a positive correlation was found between TILs and survival prognosis for HER2+ and TNBC subtypes, while for luminal subtypes it was a negative correlation. The predictive value of TILs in the neoadjuvant setting is established for HER2+, TNBC subtypes. In the case of using TILs as a predictive factor for HER2-targeted therapy, it remains a concern due to controversial data. For residual tumor, it is growing body of evidence about the positive correlation of TILs and prognosis for all subtypes, but data are limited. Conclusions. TILs were found to have prognostic and predictive value. However, due to the heterogeneity of breast cancer subtypes, TILs as a biomarker should be interpreted with caution. Further studies need to be carried out to determine the validity of making a clinical decision based on TILs count.

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Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy

OncoImmunology ◽

10.4161/onci.24720 ◽

2013 ◽

Vol 2 (7) ◽

pp. e24720 ◽

Cited By ~ 68

Author(s):

Sherene Loi

Keyword(s):

Breast Cancer ◽

Therapeutic Efficacy ◽

Tumor Infiltrating Lymphocytes ◽

Breast Cancer Subtypes ◽

Cancer Subtypes ◽

Infiltrating Lymphocytes

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Tumor-infiltrating lymphocytes to predict survival to anthracycline/taxane-based adjuvant chemotherapy in triple negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.1 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 1-1

Author(s):

Qiyun Ou ◽

Yunfang Yu ◽

Xiaoyun Xiao ◽

Baoming Luo

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Meta Analysis ◽

Disease Free Survival ◽

Breast Cancer Subtypes ◽

Her2 Positive ◽

Cancer Subtypes ◽

Infiltrating Lymphocytes

1 Background: Previous clinical data suggested that the tumour-infiltrating lymphocytes (TILs) were predictive in breast cancer treated with adjuvant chemotherapy; however, clinical relevance has yet to be established. We hypothesized that TILs would be associated with overall survival (OS) and disease-free survival (DFS) after anthracycline/taxane-based adjuvant chemotherapy in breast cancer subtypes. Methods: PubMed and EMBASE were searched until March 2017 for studies that investigated the association of TILs with survival for anthracycline/taxane-based adjuvant chemotherapy in breast cancer. OS and DFS were combined using random-effects meta-analysis and calculated as combined hazard ratio (HR) with 95% credible intervals (CIs). The PROSPERO registry number is CRD42017072133. Results: Twelve studies comprising 9,023 patients were eligible for analysis. Six were prospective adjuvant trials (n = 7686) and six were retrospective studies (n = 1337). Pooled analysis indicated that high TILs have no significant predictive association in overall population (DFS, HR = 0.87, 95% CI, 0.70 – 1.08; OS, HR = 0.98, 95% CI, 0.89 – 1.07), Luminal A/B (DFS, HR = 0.99, 95% CI, 0.94 – 1.04; OS, HR = 1.01, 95% CI, 0.92 – 1.12), and HER2–positive patients (DFS, HR = 0.84, 95% CI, 0.71 – 1.00; OS, HR = 0.89, 95% CI, 0.77 – 1.02), but were related to improved DFS (HR, 0.81; 95% CI, 0.73 – 0.89) and OS (HR, 0.74; 95% CI, 0.66 – 0.84) in triple negative breast cancer (TNBC) patients. Additionally, increasing TILs were not significantly associated with reduced risk of relapse in HER2-positive patient through adjuvant trastuzumab (HR, 0.97; 95% CI, 0.93 – 1.01). Conclusions: This meta-analysis provides an evidence that TILs predicts survival to anthracycline/taxane-based adjuvant chemotherapy in TNBC patients and suggests that predictive benefit seemed to be influenced by breast cancer subtypes as well.

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The Leptin Axis and Its Association With the Adaptive Immune System in Breast Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.784823 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laura García-Estevez ◽

Silvia González-Martínez ◽

Gema Moreno-Bueno

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Immune System ◽

Immune Cells ◽

Leptin Receptor ◽

Adaptive Immune System ◽

Tumor Infiltrating Lymphocytes ◽

Cancer Subtypes ◽

Adaptive Immune ◽

Infiltrating Lymphocytes

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

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Prediction of Distant Metastatic Recurrence by Tumor-Infiltrating Lymphocytes in Hormone Receptor-Positive Breast Cancer

10.21203/rs.3.rs-52489/v1 ◽

2020 ◽

Author(s):

Koji Takada ◽

Shinichiro Kashiwagi ◽

Yuka Asano ◽

Wataru Goto ◽

Tamami Morisaki ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Univariate Analysis ◽

Tumor Infiltrating Lymphocytes ◽

Distant Metastases ◽

University Hospital ◽

Metastatic Recurrence ◽

Cancer Subtypes ◽

Hormone Receptor Positive ◽

Infiltrating Lymphocytes

Abstract Background: Breast cancer subtypes are known to have different sites of metastatic recurrence. Distant metastases are often seen during the post-operative course in patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer (HER2BC) and triple-negative breast cancer (TNBC) while being relatively rare in those with hormone receptor-positive and HER2-negative breast cancer (HR+HER2-BC). Tumor-infiltrating lymphocytes (TILs) can serve as an index to monitor tumor immune microenvironment and possibly predict the prognosis and therapeutic effect in breast cancer. This study aimed to investigate the correlation between TIL density and recurrence site in HR+HER2-BC.Methods: Four-hundred and seventy-one patients with HR+HER2-BC underwent surgery as the first treatment and received adjuvant endocrine therapy except adjuvant chemotherapy at the Osaka City University Hospital from April 2007 to October 2015. To evaluate tumor morphology and examine TILs, needle biopsy specimens were used. Morphological assessment was conducted using conventional hematoxylin and eosin staining.Results: Forty-two patients had a recurrence of breast cancer. In patients with no TIL density, local recurrence was significantly less (p = 0.022), while distant metastases were significantly more (p = 0.015) compared to those in patients with TIL density. Therefore, for the prediction of distant metastases in HR+HER2-BC without chemotherapy, TILs could be used as predictors in univariate analysis (p = 0.015, odds ratio [OR] = 0.127), although not as independent factors (p = 0.285, OR = 0.144).Conclusions: We concluded that TILs may be able to predict distant metastatic recurrence in stages I–II of HR+HER2-BC.

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Prognostic implications of stromal tumor-infiltrating lymphocytes and programmed death ligand 1 expression in HER2-positive invasive breast cancer

10.21203/rs.3.rs-29327/v1 ◽

2020 ◽

Author(s):

Xinran Wang ◽

Ningning Zhang ◽

Shi LI ◽

Yueping Liu

Keyword(s):

Breast Cancer ◽

Tumor Infiltrating Lymphocytes ◽

Tissue Microarrays ◽

Her2 Positive ◽

Cancer Subtypes ◽

Her2 Positive Breast Cancer ◽

Programmed Death ◽

Tumor Immune Microenvironment ◽

Infiltrating Lymphocytes ◽

Positive Breast Cancer

Abstract Background: Tumor infiltrating lymphocytes (TILs) are known to be an important prognostic factor of specific breast cancer subtypes. However, to date, PD-L1(SP142)expression and tumor-infiltrating lymphocytes (TILs) has been only minimally reported in HER2-positive breast cancer cases.Methods In this study, CD8,CD4 and PD-L1༈SP142༉ were performed on tissue microarrays (TMA) representing 156 pretreatment cases of HER2-positive invasive breast carcinoma, including 55 hormone receptor (HR)-negative BC patients diagnosed from January 2010 to September 2015.Clinical data were collected, all cases were with complete follow-up data (23 recurrence and 2 deaths). The concordance rate in the tumor immune microenvironment(TIME) classification based on the PD-L1༈SP142༉expression status and CD8/CD4 + TILs count was analyzed.Results PD-L1 expression was identified in 49 cases (31.4%) in immune cells. We found there was no association was found between PD-L1 expression and DFS, but TIME classification was associated with DFS.Conclusion CD4 + and CD8 + lymphocyte infiltration was related to DFS in HER2-positive breast cancer.

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Prognostic implications of stromal tumor-infiltrating lymphocytes and programmed death ligand 1 expression in HER2-positive invasive breast cancer

10.21203/rs.3.rs-29327/v2 ◽

2020 ◽

Author(s):

Xinran Wang ◽

Ningning Zhang ◽

Shi LI ◽

Danjing Yin ◽

Yueping Liu

Keyword(s):

Breast Cancer ◽

Tumor Infiltrating Lymphocytes ◽

Tissue Microarrays ◽

Her2 Positive ◽

Cancer Subtypes ◽

Her2 Positive Breast Cancer ◽

Programmed Death ◽

Tumor Immune Microenvironment ◽

Infiltrating Lymphocytes ◽

Positive Breast Cancer

Abstract Background: Tumor infiltrating lymphocytes (TILs) are known to be an important prognostic factor of specific breast cancer subtypes. However, to date, PD-L1（SP142）expression and tumor infiltrating lymphocytes (TILs) has been only minimally reported in HER2-positive breast cancer cases. Methods: In this study, CD8,CD4 and PD-L1（SP142） were performed on tissue microarrays (TMA) representing 156 pretreatment cases of HER2-positive invasive breast carcinoma. Clinical data were collected, all cases were with complete follow-up data (23 recurrence and 2 deaths). The concordance rate in the tumor immune microenvironment(TIME) classification based on the PD-L1（SP142）expression status and CD8/CD4+TILs count was analyzed. Results: PD-L1 expression was identified in 49 cases (31.4%) in immune cells. We found there was no association was found between PD-L1 expression and DFS, but TIME classification was associated with DFS. Conclusion TIME-CD4 and TIME-CD8 lymphocyte infiltration was related to DFS in HER2-positive breast cancer.

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Association of tumor infiltrating lymphocytes with pathological response after neoadjuvant therapy in breast cancer: A retrospective study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12621 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12621-e12621

Author(s):

Punita Grover ◽

Kim Phan ◽

Tara Magge ◽

Andrew Chou ◽

Rand Naffouje ◽

...

Keyword(s):

Breast Cancer ◽

Retrospective Study ◽

Neoadjuvant Therapy ◽

Univariate Analysis ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Grade ◽

Cancer Subtypes ◽

Pre Treatment ◽

Grade 3 ◽

Infiltrating Lymphocytes

e12621 Background: Tumor infiltrating lymphocytes (TILs) are thought to represent favorable host anti-tumor immunity and play an important role in mediating response to chemotherapy in breast cancer. TILs are heterogenous across breast cancer subtypes and are increasingly being studied as prognostic and predictive biomarkers. We undertook a retrospective study to establish the relationship between pre-treatment density of TILs and subsequent quality of response to neoadjuvant chemotherapy in patients with early-stage breast cancer. Methods: We retrospectively identified women with breast cancer who had received neoadjuvant therapy (NAT) at the University of Cincinnati from 2012-2018. Clinical and pathological variables were extracted from medical records. Pre-treatment core biopsies were assessed for intra-tumoral TILs through independent pathology review and were graded as mild (grade 1), moderate (grade 2) or severe (grade 3). Post-treatment resection samples were assessed for pathological complete response (pathCR). Univariate analysis was done to determine the association between TILs and pathCR. Results: We identified 148 patients with breast cancer who received NAT, median age 53 years (25-90), 77 were Caucasian. 32 patients had stage I disease at diagnosis, 87 stage II and 29 stage III. Most patients had tumor grade 2 (n=50) or 3 (n=91). 50 patients were HER2+, 65 ER/PR+ HER2- (HR+) and 33 had triple negative breast cancer (TNBC). 69 patients received anthracycline based NAT, 29 non-anthracycline based NAT and all HER2+ patients received anti-HER2 therapy. 72 patients had TILs grade 1, 54 grade 2 and 22 had grade 3. 50 patients achieved pathCR. On univariate analysis grade 2 and 3 TILs were associated with higher likelihood of pathCR compared to grade 1 (42.1% vs 25%, OR 2.18, [1.08 – 4.4], p = 0.029). There was no difference in pathCR between grade 2 and grade 3 TILs (40.7% vs 45.5%, OR 1.21 [0.45-3.29], p=0.12). Tumor grade 3 was associated with higher pathCR than grade 1 or 2 (41.8 vs 21.1%, OR 2.69 [1.26-5.75], p=0.01). Amongst breast cancer subtypes, pathCR was lower in HR+(13.8%) compared to TNBC (45.5%) or HER2+ (52%) with OR 0.15 (0.06-0.36), p<0.01. Age, race, stage and type of chemotherapy were not associated with pathCR. On multivariate analysis, none of the variables retained significance. Conclusions: Our analysis shows that increased TILs density (grade 2 or 3) and higher tumor grade are associated with pathCR whereas HR+ breast cancer have a lower rate of pathCR after NAT. Immune characterization of TILs might be helpful in further refining the prognostic impact of TILs.[Table: see text]

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