Biological characteristics and prognostic value of Tfh-like cells in the tumor tissue of breast cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 5-5
Author(s):  
Linxiaoxi Ma ◽  
Liang Guo ◽  
Shyamal Goswami ◽  
Xiaoming Zhang ◽  
Jiong Wu
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Prognostic Value ◽  
Cell Subpopulation ◽  
Multiparameter Flow Cytometry ◽  
Cancer Center ◽  
Low Grade ◽  
Ki 67 ◽  
High Level ◽  
Er Expression

5 Background: T follicular helper (Tfh) cells formed in germinal center are CXCR5+ICOS+PD-1hiBcl-6+CXCL13+IL-21+CD4+ T cells. They have been identified in different types of tumors. However, it still remains unclear in breast cancer, with one indicating the positive prognostic value of 8-gene Tfh signature. Methods: Freshly resected invasive breast cancer tissues from Fudan University Shanghai Cancer Center of all 386 patients were collected during 03/2015 to 05/2017. Data was analyzed based on the result from Multiparameter Flow Cytometry and IHC. The correlation between Tfh-like cells and clinicopathological characteristics in breast cancer was examined with t test or one way ANOVA with Tukey’s multiple comparisons test. Results: A subpopulation of PD1hiCD4+ T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13. Tfh-like cells were of a high level of ICOS but negative for CXCR5. They had high levels of activated molecules such as CD38, CD71, CD95 and HLADR, high levels of suppressive markers as Tim3, TIGIT, and LAG3 and high level of proliferation marker Ki-67, specifically secreting cytokine IL-21 with stimulation. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P < 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1hiBcl6+CXCL13+CD4+IL-21+ T cell subpopulation. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.

Prognostic value of Tfh-like cells in breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14285-e14285
Author(s):  
Linxiaoxi Ma ◽  
Liang Guo ◽  
Shyamal Goswami ◽  
Xiaoming Zhang ◽  
Jiong Wu
Keyword(s):  
Breast Cancer ◽  
Prognostic Value ◽  
Triple Negative ◽  
Cell Subpopulation ◽  
Her2 Overexpression ◽  
Luminal A ◽  
Ki 67 ◽  
Luminal B ◽  
Tfh Cells ◽  
Er Expression

e14285 Background: The treatment of breast cancer, one of the most common malignant tumors for female, focuses on the combined treatments based on subtypes including Luminal A, Luminal B, HER2 overexpression and triple negative. Given that none of those subtypes takes into consideration of immunological parameters, it is valuable to explore the biological characteristics and prognostic value of immune cells in breast caner. T follicular helper cells (Tfh cells) have been identified in different types of tumors with rare datas in breast cancer. One of them indicated the positive prognostic value of 8-gene Tfh signature. Exploration of Tfh cells may provide new clues to the potential immunotherapies in breast cancer. Methods: Freshly resected invasive breast cancer tissue from Fudan University Shanghai Cancer Center were collected during 06/2015 to 05/2017. Patients were divided into Luminal A (N = 61), Luminal B (HER2-) (N = 138), Luminal B (HER2+) (N = 72), HER2+ (non-luminal) (N = 57) and triple negative (N = 58) based on St Gallen International Expert Consensus. Results: A subpopulation of PD1hiCD4+ T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13, confirmed by IHC. Phenotypes of those cells were checked by flow cytometry. Tfh-like cells were of a high level of ICOS but negative for CXCR5, suggesting that they were atypical Tfh cells. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P < 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). Patients with HER2+ (non-luminal) had higher frequency of Tfh-like cells than those with Luminal A (difference, 5.34; P = 0.0146). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1hiBcl6+CXCL13+CD4+ T cell subpopulation, which specifically secretes cytokine IL-21 as Tfh-like cells. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.

Analysis of Low Estrogen Receptor (ER+) Breast Carcinomas in a Large Community Breast Cancer Center in Northern California

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S26-S27
Author(s):  
G Bulusu ◽  
K Duncan ◽  
A Wheeler
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Histological Grade ◽  
Statistical Significance ◽  
Cancer Center ◽  
Pathology Report ◽  
Breast Cancers ◽  
Breast Carcinomas ◽  
Ki 67 ◽  
Er Positive

Abstract Introduction/Objective Estrogen Receptor (ER) expression in breast cancers is a crucial factor for endocrine therapy in patients with tumors expressing ER in ≥1% of tumor cells. The 2019 guidelines published by ASCO/CAP states that breast cancers that have a 1% to 10% of cells staining Estrogen Receptor (ER) positive should be reported as ER Low Positive cases. This study aims to address this subset of low-positive ER tumors and compare the clinical features to other known breast cancer subtypes. Methods/Case Report We conducted a retrospective review of a prospectively maintained breast cancer registry from 2013 to 2021 at Mills-Peninsula Medical Center, a Sutter Health Affiliate. The study reviewed patient charts with respect to the pathology report, operative report, chemotherapy regimen, and clinical outcomes. Statistical analyses were conducted using R Project for Statistical Coding, with The Student’s T-test used to compare continuous variables. Two-sided P values less than 0.05 indicate statistical significance. Results (if a Case Study enter NA) Our study identified 1316 cases of invasive breast carcinomas, of which 29 (2.16%) demonstrated ER Low-Positive expression. We aimed to evaluate the clinical and pathological features, such as histological grade, ER, PR, HER-2, Ki-67%, and patient age for these tumors. We found that ER Low-Positive tumors demonstrated higher mean histological grade morphology (2.5 out of 3, p&lt;0.001) that was similar to that of Triple Negative Breast Cancers (TNBC) (3 of 3, p&lt;0.001) than to High ER-Positive (1.6 of 3, p&lt;0.001) cancers. Further observations, through examining proliferation rates by utilizing the Ki-67 index, indicate comparative trends between the ER Low-Positive cohort and the TNBC cohort. Conclusion The results suggest that the ER Low-Positive carcinomas, despite reported as ER-positive cases, present with similar clinicopathological features to those of ER-negative tumors. Through this study and future research, we would like to emphasize a stricter set of guidelines that can be adopted to reduce variability for reporting biomarkers. This standardization will allow oncologists to provide more appropriate treatment options and improve the quality of patient care.

206 An immune-competent tumor organoid platform to test novel immune checkpoint combinations targeting the receptor CD47 in triple negative breast cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A222-A222
Author(s):  
Elizabeth Stirling ◽  
Ethan Willey-Shelkey ◽  
Adam Wilson ◽  
Aleksander Skardal ◽  
Pierre Triozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Granzyme B ◽  
Tumor Burden ◽  
Cancer Center ◽  
Murine Models ◽  
Patient Response ◽  
Tumor Immunogenicity ◽  
Cellular Bioenergetics ◽  
Glycolytic Rate

BackgroundImmune checkpoint blockade therapy targeting PD-L1 has recently been approved for metastatic triple negative breast cancer (TNBC) patients. However, a 7% response rate calls for better models and strategies to stimulate TN-tumor immunogenicity to increase patient response. Overexpression of the receptor CD47 impairs innate and adaptive tumor immunosurveillance when engaged to its counter receptor SIRPα or ligand thrombospondin-1. Co-expression of CD47 and PD-L1 is implicated with disease progression in TNBC patients. We examined through murine models and tumor organoid platforms whether targeting CD47 sensitizes TNBC tumors to PD-L1 therapy, focusing on the modulation of cellular bioenergetics as a potential mechanism and potentially predict response.MethodsThe effects of targeting CD47 and PD-L1 were examined through orthotopic syngenic 4T1 and EMT-6 TNBC murine models. Due to predicting patient therapeutic response challenges, tumor organoid platforms investigated mechanisms of tumor sensitization to anti-PD-L1 by targeting CD47. Organoids were constructed by embedding murine TNBC tumor tissue and AH1 CD8+ T cells in a specialized ECM mimicking hydrogel. Immunohistochemistry was performed on organoid, human and murine TNBC tumor tissue. Cellular bioenergetics was analyzed through Seahorse® bioanalyzer.ResultsStaining of human TNBC biopsies found elevated CD47 expression, signifying a potential therapeutic target. Targeting CD47 or in combination with anti-PD-L1 resulted in decreased tumor volume and weight in a TNBC murine model. The decrease in tumor burden was correlated with increased intratumoral granzyme B secreting CD8+ T cells. Additionally, targeting CD47 within organoids increased IFNγ and granzyme B released, indicating enhanced CD8+ T cell cytolytic capacity. Differential cellular bioenergetics was observed between cancer and T cells suggesting a shift in metabolism in the tumor microenvironment. CD47 targeted T cells had an increased glycolytic rate compared to WT T cells. Conversely CD47 targeted TNBC cells had a decreased glycolytic rate, which may be correlated with decreased PD-L1 expression.ConclusionsTargeting CD47 enhanced granzyme B and IFNγ expression suggesting potential mechanisms to increase tumor immunogenicity. CD47 targeted monotherapy or combination with anti-PD-L1 preserves T cell bioenergetics and antitumor function, resulting in decreased TNBC tumor burden. Alternatively, CD47 targeted TNBC had a decreased glycolytic rate and decreased PD-L1 expression, which is reported to regulate glycolysis through Akt/mTOR signaling. Targeting CD47 on T cells enhances their bioenergetics and antitumor function while decreasing TNBC cell bioenergetics, making them more susceptible to immune cell killing. Our data indicates that CD47 targeted monotherapy or combination with anti-PD-L1 may enhance TNBC patient response and improve overall survival.AcknowledgementsDSP and SS are supported by the Wake Forest Comprehensive Cancer Center Breast Cancer Center of Excellence Pilot Award. DSP is also supported by the ASTRO-BCRF Career Development Award (637969) while ERS is supported by NIGMS T32 (GM127261).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.

Phase II breast cancer chemoprevention study with celecoxib in women at increased risk for breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1010-1010
Author(s):  
B. Arun ◽  
V. Valero ◽  
G. Yin ◽  
G. Babiera ◽  
J. L. Murray ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Atypical Hyperplasia ◽  
Post Treatment ◽  
Short Term ◽  
Ki 67 ◽  
High Risk Women ◽  
Before And After ◽  
The Difference ◽  
Er Expression

1010 Background: Short-term chemoprevention trials offer a convenient model to screen chemopreventive agents and identify endpoint biomarkers. One of the potential agents is celecoxib (C), which has antiproliferative and apoptosis inducing properties. In this prospective study, our primary aim was to evaluate changes in proliferation induced by C in breast tissue of high risk women. Here, we report changes in estrogen receptor (ER) proliferation index. Methods: 42 eligible high risk women were enrolled into the study, underwent fine needle aspiration (FNA) and started celecoxib treatment at 400 mg BID. Median age: 51.9 years. Risk factors: Gail risk > 1.67% (n=13), lobular carcinoma insitu (n=13), atypical hyperplasia (n=11), previous history of breast cancer (n=5). For ER and Ki-67 testing, thin preparations slides were incubated with primary mouse monoclonal antibody 6F11 against the ER and clone MIB-1, respectively. Appropriate negative and positive controls were included. At least 100 epithelial cells were evaluated per slide. Immunoreactivity for each marker was scored as the percentage of positive nuclei. We assessed the difference in ER and Ki-67 levels before and after treatment using a Wilcoxon signed rank test. Results: The average pre-treatment ER expression in FNA samples was 35.9% and Ki-67 was 2.4%. 19 (45%) showed hyperplasia or atypical hyperplasia. 39 patients underwent also post-treatment FNAs. The pre-and post treatment ER expression in this group was 35.7% (range 0–100%) and 27.4% (range: 0–100%), respectively. The difference in ER levels was statistically significant (p = 0.04). Twenty-six patients had Ki-67 levels measured both before and after treatment. The median difference in Ki-67 levels was 0 (range 0- 5). This change was not statistically significant (p = 0.63). Conclusions: We have completed accrual to a prospective short-term chemoprevention trial with celecoxib. We have found a significant downregulation of ER expression with 6 months celecoxib. Since ER expression is a marker of proliferation, this finding confirms celecoxibs antiproliferative properties. Currently, we have not observed a change in Ki-67; this could be partly due to the small number of samples and the fact that Ki-67 is low in normal epithelium. [Table: see text]

Prognostic value of Ki-67 labeling index according to age in patients with non-metastasic triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12118-e12118
Author(s):  
Victor Zenzola ◽  
María Antonia Cabezas-Quintario ◽  
Andrea Correa ◽  
Irene Moreno ◽  
Manuel Pedregal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Roc Curve ◽  
Prognostic Value ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Time Dependent ◽  
Clinicopathologic Characteristics ◽  
Ki 67 ◽  
Poor Prognostic Factor

e12118 Background: The prognostic value of Ki67 in triple negative breast cancer (TNBC) is yet unclear because the cut-off points employed differ widely and its predictive effect may vary according to age. The purpose of this study was to analyze the role of Ki-67 among patients with TNBC, and determined the optimal Ki-67 cut-off point to demonstrate its prognostic relevance associated with patient age and treatment strategy. Methods: 201 patients treated for primary TNBC from 1999 to 2014 were identified from the breast surgery database. Clinicopathologic characteristics and outcomes were compared between patients treated with neoadjuvant or adjuvant chemotherapy. We used time-dependent receiver operating characteristic (ROC) curve and time-dependent area under the ROC curve (AUC) to evaluate the discriminative ability of Ki-67 at 3 and 5 years of follow up. A Ki-67 cut-off point was set up to maximize sensitivity and specificity. Interaction effect between age and Ki-67 on disease-free survival (DFS) and overall survival (OS) was evaluated by stratified analysis. Results: There was a non-significant Ki-67 cut off value to predict OS and DFS at 3 and 5 years neither in the whole serie (201) nor in the adjuvant group (125), and only a slightly better threshold for DFS in the neoadjuvant one (N = 46) at 5 years (AUC = 0.697). According to the coordinates of the ROC curves, the best cut-off point for Ki-67 was 60%. In the multivariate analysis (COX proportional hazards regression), high Ki-67 ( > 60%), was a poor prognostic factor for DFS in patients > 40 yo. Among the patients < 40 yo, high Ki-67 was a better prognosis factor. Conclusions: Our data suggest that a threshold of Ki-67 of 60% could provide a usefull tool to define patients with significantly different outcome in TNBC.

scholarly journals Prognostic Value of the Nodal Ratio and Ki-67 Expression in Breast Cancer Patients Treated with Postmastectomy Radiotherapy

2013 ◽  
Vol 16 (3) ◽  
pp. 274 ◽  
Author(s):  
Tae Ryool Koo ◽  
Keun Yong Eom ◽  
Eun Young Kang ◽  
Yu Jung Kim ◽  
Sung Won Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Prognostic Value ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Postmastectomy Radiotherapy ◽  
Nodal Ratio
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