scholarly journals PathoNet introduced as a deep neural network backend for evaluation of Ki-67 and tumor-infiltrating lymphocytes in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Farzin Negahbani ◽  
Rasool Sabzi ◽  
Bita Pakniyat Jahromi ◽  
Dena Firouzabadi ◽  
Fateme Movahedi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Deep Learning ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Detection ◽  
Ki 67 ◽  
Link Type ◽  
Proposed Model ◽  
Response To Chemotherapy ◽  
Individual Variations ◽  
Infiltrating Lymphocytes

AbstractThe nuclear protein Ki-67 and Tumor infiltrating lymphocytes (TILs) have been introduced as prognostic factors in predicting both tumor progression and probable response to chemotherapy. The value of Ki-67 index and TILs in approach to heterogeneous tumors such as Breast cancer (BC) that is the most common cancer in women worldwide, has been highlighted in literature. Considering that estimation of both factors are dependent on professional pathologists’ observation and inter-individual variations may also exist, automated methods using machine learning, specifically approaches based on deep learning, have attracted attention. Yet, deep learning methods need considerable annotated data. In the absence of publicly available benchmarks for BC Ki-67 cell detection and further annotated classification of cells, In this study we propose SHIDC-BC-Ki-67 as a dataset for the aforementioned purpose. We also introduce a novel pipeline and backend, for estimation of Ki-67 expression and simultaneous determination of intratumoral TILs score in breast cancer cells. Further, we show that despite the challenges that our proposed model has encountered, our proposed backend, PathoNet, outperforms the state of the art methods proposed to date with regard to harmonic mean measure acquired. Dataset is publicly available in http://shiraz-hidc.com and all experiment codes are published in https://github.com/SHIDCenter/PathoNet.

scholarly journals High expression of E-cadherin and Ki-67 associated with functional/dysfunctional phenotypes of tumor-infiltrating lymphocytes among Chinese patients with operable breast cancer

2018 ◽  
Vol 46 (12) ◽  
pp. 5219-5227 ◽  
Author(s):  
Ruibin Wang ◽  
Feng Shi ◽  
Lin Zhao ◽  
Yanjie Zhao ◽  
Guangjiang Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Cross Sectional Study ◽  
Clinicopathological Features ◽  
Chinese Patients ◽  
Ki 67 ◽  
Cross Sectional ◽  
Cell Counts ◽  
Infiltrating Lymphocytes ◽  
E Cadherin

Objective Breast cancer has become the most common cancer in women in China, and the clinicopathological features differ from those in Western patients. This study was performed to investigate the distribution of programmed cell death protein 1 (PD-1)+/PD-1− tumor-infiltrating lymphocytes (TILs) and its association with clinicopathological features among Chinese patients with breast cancer. Methods In total, 133 consecutive patients with primary breast cancer were recruited into this cross-sectional study from 2012 to 2013. TILs were measured by cell counts under high-power fields (HPFs). Immunohistochemistry was used to detect PD-1 expression on tumor-infiltrating lymphocytes in the microenvironment. Results The median cell counts of the overall TILs, PD-1+ TILs, and PD-1− TILs were 80, 18, and 55/HPF, respectively. The number of PD-1− TILs was significantly lower in older than younger patients (50 vs. 60/HPF). Patients with positive E-cadherin expression had more PD-1− TILs than patients with negative E-cadherin expression (57 vs. 27/HPF). The Ki-67 index was positively correlated with the cell counts of PD-1+ TILs, and the correlation coefficient was 0.29. Conclusions PD-1 expression on TILs had different clinicopathological features in Chinese patients with breast cancer. E-Cadherin expression was associated with PD-1− TILs; however, Ki-67 expression was associated with PD-1+ TILs.

scholarly journals Cell Counts, rather than Proportion, of CD8/PD-1 Tumor-Infiltrating Lymphocytes in a Tumor Microenvironment Associated with Pathological Characteristics of Chinese Invasive Ductal Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Qingkun Song ◽  
Feng Shi ◽  
Maya Adair ◽  
Hong Chang ◽  
Xiudong Guan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Axillary Lymph Node ◽  
Tumor Infiltrating Lymphocytes ◽  
Axillary Lymph Node Metastasis ◽  
Axillary Lymph ◽  
Ki 67 ◽  
Invasive Ductal Breast Cancer ◽  
Cell Counts ◽  
Infiltrating Lymphocytes

Objective. This study is aimed at investigating the association of exhausted CD8+ tumor-infiltrating lymphocytes with clinic-pathological factors. Methods. 133 patients diagnosed with primary invasive ductal breast cancer were recruited into the cross-sectional study consecutively. Immunohistochemistry was used to detect biomarker expression on formalin-fixed and paraffin-embedded sections. Double staining of CD8 and PD-1 was conducted on lymphocytes. Results. The proportion of CD8+/PD-1- TILs was 16% among patients with axillary lymph node metastasis, significantly lower than those without metastasis (24%). The expression of CK7, CK20, or Ki-67 was not related with the proportion of phenotypes of CD8/PD-1 TILs. Younger patients had more cell counts of CD8+/PD-1- TILs than elderly patients (18/HPF vs. 9/HPF, p<0.05). Patients with axillary lymph node metastasis had less CD8+/PD-1- TILs than those without metastasis (11/HPF vs. 27/HPF, p<0.05). Median counts of CD8+/PD-1- TILs among patients with CK20 and E-Cad expression were 33/HPF and 14/HPF, significantly higher than those among patients with negative CK20 (16/HPF) and E-Cad expression (6/HPF). Ki-67 index had a significant correlation with cell counts of CD8+/PD-1+ TILs and CD8+/PD-1- TILs, and the correlation coefficients were 0.19 and 0.21 (p<0.05), respectively. Conclusion. The proportion of CD8+/PD-1- TILs was related with metastatic status of the axillary lymph node but cell counts of CD8+/PD-1- TILs were related with metastatic status of the axillary lymph node and expression of CK7, CK20, E-Cad, and Ki-67. Absolute cell counts, not proportion of CD8/PD-1 TILs, were more likely to distinguish clinic and pathologic characteristics of breast cancer.

scholarly journals Expression of PD-1 on CD4+ Tumor-Infiltrating Lymphocytes in Tumor Microenvironment Associated with Pathological Characteristics of Breast Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yan-Jie Zhao ◽  
Jian Zhang ◽  
Feng Shi ◽  
Zhi-Ping Hu ◽  
Jiang-Ping Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Significant Relationship ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Subsets ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Pathological Characteristics ◽  
Cell Counts ◽  
Infiltrating Lymphocytes ◽  
E Cadherin

Objective. This study aimed to investigate the correlation of CD4+/PD-1+ or CD4+/PD-1− tumor-infiltrating lymphocytes with pathological characteristics in breast cancer patients. Methods. A cross-sectional study consecutively recruited 133 patients with invasive ductal breast cancer. The expression of CD4, programmed cell death protein 1 (PD-1), CK7, CK20, E-cadherin, or Ki-67 was detected by immunohistochemistry. The associations between CD4+/PD-1+ or CD4+/PD-1− tumor-infiltrating lymphocytes and pathological characteristics were evaluated. Results. Elderly patients intended to have a lower level of CD4+/PD-1− tumor-infiltrating lymphocytes (p<0.05). Patients with positive E-cadherin expression had higher median cell counts of CD4+/PD-1− tumor-infiltrating lymphocytes than patients with negative E-cadherin expression (30/HPF versus 10/HPF, p<0.05). Counts of CD4+/PD-1+ tumor-infiltrating lymphocytes had a significant correlation with Ki-67 index that the correlation coefficient was 0.29 (p=0.001). Positive CK20 expression was related to a higher level of CD4+/PD-1− tumor-infiltrating lymphocytes than negative CK20 expression (73/HPF versus 30/HPF, p<0.05). Conclusion. CD4+/PD-1+ or CD4+/PD-1− tumor-infiltrating lymphocytes showed diverse association with pathological features of breast cancer. CD4+/PD-1+ tumor-infiltrating lymphocytes had a significant relationship with Ki-67 expression whereas CD4+/PD-1− tumor-infiltrating lymphocytes had a significant relationship with E-cadherin expression. Further studies are warranted to explore the immunomodulatory effects of phenotypes of CD4+ T cell subsets in breast cancer.

scholarly journals Immunomodulating Therapies in Breast Cancer—From Prognosis to Clinical Practice

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4883
Author(s):  
Marcus Schmidt ◽  
Anne-Sophie Heimes
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Response To Chemotherapy ◽  
Infiltrating Lymphocytes

The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98

2013 ◽  
Vol 31 (7) ◽  
pp. 860-867 ◽  
Author(s):  
Sherene Loi ◽  
Nicolas Sirtaine ◽  
Fanny Piette ◽  
Roberto Salgado ◽  
Giuseppe Viale ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Lymphocytic Infiltration ◽  
Phase Iii ◽  
Cancer Trial ◽  
Risk Of Death ◽  
Node Positive ◽  
Response To Chemotherapy ◽  
Infiltrating Lymphocytes ◽  
Reduced Risk

Purpose Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes. Patients and Methods We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. Results There was no significant prognostic association in the global nor estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). Conclusion In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.

scholarly journals Histopathological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) as Predictive Biomarker for Hormone Receptors Status, Proliferative Activity and Clinical Outcome in Her-2 Positive Breast Cancer

2021 ◽  
Vol 11 (15) ◽  
pp. 6788
Author(s):  
Giuseppe Angelico ◽  
Giuseppe Broggi ◽  
Rosario Caltabiano ◽  
Angela Santoro ◽  
Saveria Spadola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Biomarker ◽  
Nuclear Staining ◽  
Ki 67 ◽  
Stromal Tissue ◽  
Her 2 ◽  
Infiltrating Lymphocytes ◽  
Positive Breast Cancer

Background: In the present study, we evaluated the prognostic value of TILs as well their relation with clinicopathological factors in patients affected by HER-2 positive breast cancer. Methods: We evaluated 47 patients with a histologically confirmed diagnosis of invasive breast carcinoma showing an immunohistochemically confirmed (score 3+) amplification of the c-erbB-2 gene for the presence of TILs and categorized in three predefined groups of low (0–10% immune cells in stromal tissue within the tumor), intermediate (11–40%), and high TILs (>40%). Results: Low, intermediate and high TILs were found in 17/47 (36%), 23/47 (49%) and 7/47(15%) cases, respectively. It was found that 6/47 cases treated with adjuvant chemotherapy plus trastuzumab underwent progression of the disease; none of these cases exhibited high TILs. It was found that 12/47 patients with a prognostically unfavorable stage of III and IV showed low and intermediate levels of TILs, while high TILs were never observed. A significant association between intermediate/high-levels of TILs, elevated KI 67 index and hormone receptors nuclear staining was observed. High concordance in TILs distribution was observed between preoperative breast biopsies and surgical samples. Conclusions: We observed a positive correlation between the TILs and the response to both adjuvant and neoadjuvant treatments in HER-2 positive BC. High TILs were also related to increased KI-67 index and to the expression of hormone receptors.

Subpopulation composition of tumor-infiltrating lymphocytes in luminal breast cancer and its effect on effectiveness of neoadjuvant chemotherapy

2020 ◽  
pp. 32-37
Author(s):  
E. I. Kovalenko ◽  
E. V. Artamonova ◽  
T. N. Zabotina ◽  
Z. G. Kadagidze ◽  
S. G. Bagrova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Initial Level ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Prognosis ◽  
Luminal Breast Cancer ◽  
Tumor Subtype ◽  
Luminal A ◽  
Ki 67 ◽  
Infiltrating Lymphocytes

Tumor-infiltrating lymphocytes (TILs) play a key role in the formation of anti-tumor immunity and, as studies have shown, can be one of the markers of treatment effectiveness and cancer prognosis. The aim was to study the subpopulation composition of the lymphoid infiltrate in early luminal breast cancer in patients receiving neoadjuvant chemotherapy (NACT) and its effect on achieving a pathological complete response (pCR). Materials and methods. We included 24 patients who received anthracycline-taxane-contain-ing preoperative chemotherapy. The subpopulation composition of TIL was assessed in core-biopsy samples before starting NACT in all patients; after treatment, the assessment was made on postoperative material. The analysis was carried out by flow cytometry. Clinical and immunological assessment was carried out for the following seven subpopulations of lymphocytes: CD3+, CD3+CD4+, CD3+CD8+, CD4+CD127+CD25+, CD3 CD19+ CD3CD16+CD56+, CD3+CD16+CD56+. Results. The incidence pCR was 16.7 %. It was revealed that the initial level before treatment of CD3+, CD3+CD4+, CD3+CD8+, CD4+C-D127+CD25+, CD3-CD19+, CD3 CD16+CD56+, CD3+CD16+CD56+ lymphocytes did not differ depending on the stage of the disease (II or III), tumor subtype (luminal A/B) and Ki-67 level (up to 20, 20-39, 40 and more). No correlations were found between Ki-67 and TIL content. When conducting regression analysis, it was revealed that only the level of CD3+, CD3+CD8+ and CD19+ was a significant factor in achieving a pCR (p = 0.005). When an empirical subgroup was identified, which was characterized by a high content (above or equal to the median) of CD3+, CD3+CD8+ and low (below the median) CD19+ (four observations), the frequency of pCR reached 75 %. Conclusion. Thus, the initial level of T-lymphocytes (CD3+, CD3+CD8+) and B-lymphocytes (CD19+) in the tumor, regardless of the stage of the disease, tumor subtype, ki-67 index, was a predictor of high sensitivity to neoadjuvant chemotherapy of luminal breast cancer and was associated with higher frequency of pCR.

Tumor-infiltrating lymphocytes as a prognostic factor in patients with stage I to III breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12042-e12042
Author(s):  
Eduardo Richardet ◽  
Luciana Paola Acosta ◽  
Martin Paradelo ◽  
Martin Pairola ◽  
Cecilia Di Tada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factor ◽  
Adjuvant Treatment ◽  
Tumor Infiltrating Lymphocytes ◽  
Stage I ◽  
Current Evidence ◽  
Cell Phenotype ◽  
Kaplan Meier ◽  
Response To Chemotherapy ◽  
Infiltrating Lymphocytes

e12042 Background: Current evidence makes reference to the potential role that tumor-infiltrating lymphocytes (TILs) as a prognostic factor in breast cancer and numerous types of tumors. Different studies have shown that the interaction with the immune response of the host is relevant to the response to chemotherapy. TILs are cell phenotype T CD3 +, which can, in turn, stratify in cytotoxic T lymphocytes (CD8), and regulatory T cells (CD4+ CD25+ FOXP3+).Our aim was to identify whether there was a relationship between TILs and SLE in patients with stage I to III breast cancer who have undergone chemotherapy adjuvant treatment. The secondary endpoint was to analyze the association between subtype infiltrating lymphocytes (CD4 and CD8) and SLE. Methods: Retrospective and analytical study in our institution IONC. Patients with stage I to III breast cancer was analized which had standard risk factors and required adjuvant treatment with chemotherapy. 87 patients completed with the selection criteria. The infiltration degree by H/E was evaluated and CD4 and CD8 by IHQ was marked. SLE was analyzed through the Kaplan-Meier method. Results: 87 samples were analyzed, in 46 patients (52,8 %) evidenced TILs and in 41 patients (47.12%) there were no TILs in their tumor samples. SLE was higher for those patients who had TILs with respect to those patients who did not have any TILs, 45.3 months as opposed to 30.85 months respectively (p: 0,038) and these differences were statistically different. In the TILi analysis, it could observed that 91% patients not revealed infiltrations in their tumor samples.When correlating CD4 and CD8 was carried out, 33% of the patients showed CD4 TILs in their tumor samples and 49.4% evidenced CD8 TILs. There were no SLE differences regarding the presence or the absence of CD4. The high number of CD8 was associated to a higher SLE; 39.06 months as opposed to 37.5 months, but these differences were not statistically different. Conclusions: We could conclude that patients who had showed TILs in their tumor samples had a higher SLE with respect to those who did not show any infiltration and this was statistically significant. There were no differences when samples were analyzed on the presence or absence of CD4 and CD8.

Sign in / Sign up

Export Citation Format

Share Document