Significance of systemic and local immune responses to the pathological therapeutic effect of neoadjuvant chemotherapy in breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12084-e12084
Author(s):  
Ryungsa Kim ◽  
Ami Kawai ◽  
Megumi Wakisaka ◽  
Yuri Funaoka ◽  
Sayaka Sawada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Neoadjuvant Chemotherapy ◽  
Immune Responses ◽  
Nk Cells ◽  
Therapeutic Effect ◽  
Cell Activity ◽  
Multivariate Logistic Regression Analysis ◽  
Therapeutic Effects ◽  
Axillary Lymph

e12084 Background: Activation of the immune response including T lymphocytes, natural killer (NK) cells, and tumor microenvironment factors (TMEFs) is important in inducing a therapeutic response after neoadjuvant chemotherapy (NAC) in breast cancer. We examined the significance of systemic and local immune responses to the pathological therapeutic effect of NAC in breast cancer. Methods: From 2012 to 2018, 38 patients with stage II–III breast cancer received NAC with anthracyclines and taxanes followed by surgery. Therapeutic effects were evaluated according to the histopathology criteria for the assessment of therapeutic effects in breast cancer indicated by the Japanese Breast Cancer Society. Peripheral NK (pNK) cell activity was measured by chromium release assay. Levels of TMEFs were assessed by next-generation sequencing for CD4, CD8, NK, FOXP3, CTLA-4, PD-1, PD-L1, IL-2, IL-6, IL-12, IFN-γ, IL-10, TGF-β, and VEGF in FFPE sections collected from preoperative VAB samples and surgical specimens. Results: The stages, tumor subtypes, and therapeutic outcomes were as follows: II (N = 21), III (N = 17); luminal (N = 22), HER-2 positive (N = 12), TN (N = 4); G1a (N = 8), G1b (N = 13), G2a (N = 7), G2b (N = 4), G3 (i.e. complete) (N = 6). A G2 or better therapeutic effect were significantly associated with high post-NAC levels of NK, and potentially associated with higher CD4, CD8, and lower CTLA-4 after NAC. Multivariate logistic regression analysis showed that a G2 or better therapeutic effect was significantly associated with higher NK after NAC (OR = 1.07; 95% CI, 1.00–1.14; P = .0255). Disappearance of axillary lymph node metastasis was significantly associated with increased NK and pNK cell activity, as well as decreased VEGF level, and potentially associated with lower CTLA-4 after NAC. Conclusions: Increased NK cells after NAC are critical in producing a better therapeutic effect in collaboration with increased CD4 and CD8, and decreased CTLA-4 and VEGF. Systemic activation of pNK cells may improve the elimination of metastatic tumor cells in axillary lymph nodes by coordinating with release of immunosuppression derived from VEGF and activation of immune cells in the tumor microenvironment in breast cancer patients after NAC. An immune checkpoint inhibitor targeting CTLA-4 may improve NAC efficacy for breast cancer.

Gamma-interferon inducible lysosomal thiolreductase (GILT) effect on breast tumor microenvironment through regulating CXCR6/CXCL16 axis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
YinJiao Fei ◽  
MingXing Liang ◽  
Lei Li ◽  
Yuxin Song ◽  
Zhen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Western Blot ◽  
Cell Line ◽  
Gamma Interferon ◽  
Gene Set Enrichment Analysis ◽  
High Expression ◽  
Axillary Lymph ◽  
Potential Biomarker

e15081 Background: Gamma-interferon Inducible Lysosomal Thiolreductase (GILT) is constitutively expressed in most antigens endocytosed by antigen presenting cells (APCs), and its function is to catalyze the reduction of disulfide (S-S) bonds in protein substrates. The cytokine CXCL16 is one of the only two known plasma membrane chemokines which induces chemotaxis of activated T cells and bone marrow plasma cells in tumor microenvironment. It contains a free end folded by two sulfur bonds and therefore could also be a zymolyte of GILT. Previous studies found that specific receptor of CXCL16, CXCR6, was significantly overexpressed in breast cancer tissues and metastatic axillary lymph nodes. We suppose whether CXCR6/CXCL16 axis is regulated by GILT and affect tumor microenvironment, thereby eliciting specific anti-tumor immune responses in breast cancer (BC). Methods: GILT expression in BC was evaluated using publicly available data from The Cancer Genome Atlas (TCGA). GILT gene was analyzed in UALCAN ( http://ualcan.path.uab.edu/analysis-prot.html ) . In vitro, Immunohistochemistry (IHC) was conducted to examine the location and relation of GILT and CXCR6. Gene Set Enrichment Analysis (GSEA) was performed to mine the biological pathways involved in BC related GILT regulatory network. The expression of GILT at protein and RNA levels were detected by Western Blot and RT-PCR assay. Overexpression and knockdown of GILT in BC cell lines was carried out to further analyzed the correlation between GILT and CXCL16/CXCR6. Results: TCGA database showed that GILT expression was increased in the stroma of BC compared with normal, and was correlated to shorter BC overall survival. GSEA suggested that the expression of GILT was associated with chemotactic factors. Pearson analysis and IHC showed GILT had a strong correlation with CXCL16/CXCR6 axis in the aspect of angiogenesis and immunity. qRT-PCR and Western Blot assay also revealed that GILT had high expression in BC. Besides, patients with high expression of GILT in IHC simultaneously showed high immunoreactive to macrophage markers, which was related to neovascularization and anti-tumor immune responses. Compared with the normal breast cell line MCF-10A, GILT protein had high expression in Hs578T and low expression in MDA-MB-231 cell line. GILT was overexpressed in MDA-MB-231 and knockdown in Hs578T. Result showed that high level GILT promoted the production of CXCL16/CXCR6,while GILT siRNA knockdown inhibited the production of CXCL16/CXCR6. Conclusions: GILT could catalyze CXCL16 in BC, function as a key mechanism to affect tumor microenvironment through CXCR6/CXCL16 pathway. GILT-activated CXCL16 levels showed a strong connection with unfavorable outcomes in BC, which could be a potential biomarker of prognosis and a novel therapeutic target.

scholarly journals Systemic immune reaction in axillary lymph nodes adds to tumor-infiltrating lymphocytes in triple-negative breast cancer prognostication

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Fangfang Liu ◽  
Thomas Hardiman ◽  
Kailiang Wu ◽  
Jelmar Quist ◽  
Patrycja Gazinska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Axillary Lymph Nodes ◽  
Axillary Lymph ◽  
Her2 Positive ◽  
Local Immunity ◽  
Infiltrating Lymphocytes

AbstractThe level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We previously demonstrated that histological alterations in axillary lymph nodes (LNs) carry clinical relevance. Here, we capture local immune responses by scoring TILs at the primary tumor and systemic immune responses by recording the formation of secondary follicles, also known as germinal centers, in 2,857 cancer-free and involved axillary LNs on haematoxylin and eosin (H&E) stained sections from a retrospective cohort of 161 LN-positive triple-negative and HER2-positive breast cancer patients. Our data demonstrate that the number of germinal center formations across all cancer-free LNs, similar to high levels of TILs, is associated with a good prognosis in low TILs TNBC. This highlights the importance of assessing both primary and LN immune responses for prognostication and for future breast cancer research.

scholarly journals Analysis of CK5/6 and EGFR and Its Effect on Prognosis of Triple Negative Breast Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Zhen Wang ◽  
Lei Liu ◽  
Ying Li ◽  
Zi’an Song ◽  
Yi Jing ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regression Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Multivariate Logistic Regression Analysis ◽  
Pathological Examination ◽  
Cox Regression Analysis ◽  
Tumor Stages

BackgroundTriple-negative breast cancer (TNBC) is considered to be higher grade, more aggressive and have a poorer prognosis than other types of breast cancer. Discover biomarkers in TNBC for risk stratification and treatments that improve prognosis are in dire need.MethodsClinical data of 195 patients with triple negative breast cancer confirmed by pathological examination and received neoadjuvant chemotherapy (NAC) were collected. The expression levels of EGFR and CK5/6 were measured before and after NAC, and the relationship between EGFR and CK5/6 expression and its effect on prognosis of chemotherapy was analyzed.ResultsThe overall response rate (ORR) was 86.2% and the pathological complete remission rate (pCR) was 29.2%. Univariate and multivariate logistic regression analysis showed that cT (clinical Tumor stages) stage was an independent factor affecting chemotherapy outcome. Multivariate Cox regression analysis showed pCR, chemotherapy effect, ypT, ypN, histological grades, and post- NAC expression of CK5/6 significantly affected prognosis. The prognosis of CK5/6-positive patients after NAC was worse than that of CK5/6-negative patients (p=0.036). Changes in CK5/6 and EGFR expression did not significantly affect the effect of chemotherapy, but changes from positive to negative expression of these two markers are associated with a tendency to improve prognosis.ConclusionFor late-stage triple negative breast cancer patients receiving NAC, patients who achieved pCR had a better prognosis than those with non- pCR. Patients with the change in expression of EGFR and CK5/6 from positive to negative after neoadjuvant chemotherapy predicted a better prognosis than the change from negative to positive group.

Role of Ultrasound in the Diagnosis of Lymph Node Status in Axillary Lymph Node Metastases in Breast Cancer undergoing Neoadjuvant Chemotherapy

2020 ◽  
Author(s):  
Yizhen Zhou ◽  
Lei Zhang ◽  
Zining Jin ◽  
Hailan Yu ◽  
Siyu Ren ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
Axillary Lymph Node ◽  
Lymph Node Status ◽  
Axillary Lymph ◽  
Short Axis ◽  
Breast Cancer Patients ◽  
Axillary Ultrasound

Abstract Background:Axillary ultrasound (AUS) is one of the important bases for evaluating the axillary status of breast cancer patients. And it would be helpful for the reassessment of axillary lymph node status in these patients after neoadjuvant chemotherapy(NAC) and guide the selection of their axillary surgical options.The purpose of this study was to evaluate the diagnostic performance of ultrasound,and to find out the factors related to the outcome of ultrasound.Methods:In this retrospective analysis, 172 patients (one bilateral breast cancer) with breast cancer and clinical positive axillary nodes, were enrolled. After NAC, all patients received mastectomy and axillary lymph node dissection (ALND). AUS was used before and after NAC to assess the axilla status. Results:Of the 173 axillae, 137 (79.19%) had pathological metastasis after NAC. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of axillary ultrasound in this cohort were 68.21%, 69.34%, 63.89%, 87.96% and 35.38% respectively. Univariate analysis showed that primary axillary lymph node(ALN) short axis, progesterone receptors, hormone receptors, the tumor status after NAC, tumor reduction rate, ALN short axis after NAC, physical examination of axilla after NAC and pN impacted the results of AUS(P = 0.000 ~ 0.040). Multivariate analysis of the above indicators showed that ALN short axis after NAC and pN associated with AUS results independently. Conclusion:AUS can accurately assess axilla status after NAC in most breast cancer patients. If the short axis of ALN≥10mm and AUS negative, SLNB could be chosen. However, AUS cannot detect residual lymph node disease after NAC in a short axis of the ALN <10mm.

scholarly journals Mammography-based radiomics nomogram: a potential biomarker to predict axillary lymph node metastasis in breast cancer

2020 ◽  
Vol 93 (1111) ◽  
pp. 20191019 ◽  
Author(s):  
Hongna Tan ◽  
Yaping Wu ◽  
Fengchang Bao ◽  
Jing Zhou ◽  
Jianzhong Wan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regression Analysis ◽  
Lymph Node ◽  
Axillary Lymph Node ◽  
Multivariate Logistic Regression Analysis ◽  
Support Vector ◽  
Axillary Lymph ◽  
Features Selection ◽  
Potential Biomarker ◽  
Radiomics Signature

Objective: To establish a radiomics nomogram by integrating clinical risk factors and radiomics features extracted from digital mammography (MG) images for pre-operative prediction of axillary lymph node (ALN) metastasis in breast cancer. Methods: 216 patients with breast cancer lesions confirmed by surgical excision pathology were divided into the primary cohort (n = 144) and validation cohort (n = 72). Radiomics features were extracted from craniocaudal (CC) view of mammograms, and radiomics features selection were performed using the methods of ANOVA F-value and least absolute shrinkage and selection operator; then a radiomics signature was constructed with the method of support vector machine. Multivariate logistic regression analysis was used to establish a radiomics nomogram based on the combination of radiomics signature and clinical factors. The C-index and calibration curves were derived based on the regression analysis both in the primary and validation cohorts. Results: 95 of 216 patients were confirmed with ALN metastasis by pathology, and 52 cases were diagnosed as ALN metastasis based on MG-reported criteria. The sensitivity, specificity, accuracy and AUC (area under the receiver operating characteristic curve of MG-reported criteria were 42.7%, 90.8%, 24.1% and 0.666 (95% confidence interval: 0.591–0.741]. The radiomics nomogram, comprising progesterone receptor status, molecular subtype and radiomics signature, showed good calibration and better favorite performance for the metastatic ALN detection (AUC 0.883 and 0.863 in the primary and validation cohorts) than each independent clinical features (AUC 0.707 and 0.657 in the primary and validation cohorts) and radiomics signature (AUC 0.876 and 0.862 in the primary and validation cohorts). Conclusion: The MG-based radiomics nomogram could be used as a non-invasive and reliable tool in predicting ALN metastasis and may facilitate to assist clinicians for pre-operative decision-making. Advances in knowledge: ALN status remains among the most important breast cancer prognostic factors and is essential for making treatment decisions. However, the value of detecting metastatic ALN by MG is very limited. The studies on pre-operative ALN metastasis prediction using the method of MG-based radiomics in breast cancer are very few. Therefore, we studied whether MG-based radiomics nomogram could be used as a predictive biomarker for the detection of metastatic ALN.

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