Immunogenicity and transcriptomic biology in Nottingham histologic grade 3 breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12563-e12563
Author(s):  
Hideo Takahashi ◽  
Masanori Oshi ◽  
Mariko Asaoka ◽  
Li Yan ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cancer Biology ◽  
Histological Grade ◽  
Molecular Taxonomy ◽  
Tumor Biology ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
Related Gene ◽  
Gene Sets

e12563 Background: Cancer biology dictates disease progression and prognosis of a tumor. Histological grade has been used as a proxy of tumor biology in various cancer types, although it depends on morphological analysis of the tissue. As such, Nottingham histological grade is recently incorporated into the 8th edition of the AJCC Breast Cancer Staging. Herein, we hypothesized that Nottingham histological Grade3 breast cancer (BC) demonstrate strong immunogenicity in response to aggressive phenotypes, reflecting worse clinical outcomes. Methods: Clinicopathological data and transcriptomes were obtained from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA) Invasive breast carcinoma (BRCA) cohort, and GSE25066. While METABRIC was used as a training cohort, the other two cohorts served as validation cohorts. As TCGA did not contain pathological information, Nottingham histological grade was manually collected through the Text Information Extraction Systems (TIES). Results: 2876 patients were analyzed in this study. Grade1 tumors were 274 patients (9.5%), Grade2 tumors 1185 patients (41.2%), and Grade3 tumors 1417 patients (49.3%). Grade3 tumors were common in patients with Estrogen receptor (ER) negative (p < 0.001), with Her2 and Basal molecular subtypes by the PAM50 classifier (p < 0.001), and associated with increased MKI-67 expression (p < 0.001). Disease-free survival (DFS) was significantly worse in Grade3 tumors in all cohorts. Gene set enrichment analysis (GSEA) demonstrated that Grade3 tumors significantly enriched immune activity related gene sets as well as cell proliferation and cell cycle related gene sets. CIBERSORT also demonstrated that Grade3 BCs were infiltrated with anti-cancer macrophage M1, follicular helper T cells, and activated NK cells (all p < 0.001). Furthermore, Grade3 tumors were associated with more diverse T cell receptor (p = 0.001) and increased cytolytic activity (p < 0.001). Lastly, T cell exhaustion markers, including PD-L1, PD-1, and CTLA4, were significantly elevated in Grade3 BCs (all p < 0.001) as a negative feedback loop. Conclusions: Grade3 BCs demonstrated enhanced immunogenicity as well as aggressive transcriptomic features.

scholarly journals Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation

2020 ◽  
Vol 21 (16) ◽  
pp. 5744 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Li Yan ◽  
Jing Li Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Cancer Biology ◽  
The Cancer Genome Atlas ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
Tumor Immune Microenvironment ◽  
Er Positive

Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as “intratumoral adipocyte”. These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.

scholarly journals High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer

2020 ◽  
Vol 21 (9) ◽  
pp. 3045 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Eriko Katsuta ◽  
Masanori Oshi ◽  
Judith C. Sporn ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Biology ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Taxonomy ◽  
The Cancer Genome Atlas ◽  
P53 Pathway ◽  
Mesenchymal Transition ◽  
Gene Sets ◽  
Aggressive Cancer

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts.

scholarly journals Adipogenesis in triple-negative breast cancer is associated with unfavorable tumor immune microenvironment and with worse survival

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masanori Oshi ◽  
Yoshihisa Tokumaru ◽  
Fernando A. Angarita ◽  
Lan Lee ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Chemotherapy Response ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Set ◽  
Gene Sets ◽  
Tumor Immune Microenvironment

AbstractCancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (n = 3273), validation; TCGA (n = 1069), treatment response; GSE25066 (n = 508) and GSE20194 (n = 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8+ T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of PD-L1 and PD-L2 genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.

scholarly journals Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2559
Author(s):  
Shipra Gandhi ◽  
Masanori Oshi ◽  
Vijayashree Murthy ◽  
Elizabeth A. Repasky ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cold Stress ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
Tumor Immune Microenvironment

Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer

2018 ◽  
Vol 21 (2) ◽  
pp. 74-83
Author(s):  
Tzu-Hung Hsiao ◽  
Yu-Chiao Chiu ◽  
Yu-Heng Chen ◽  
Yu-Ching Hsu ◽  
Hung-I Harry Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Cancer Survival ◽  
Expression Profiles ◽  
Functional Gene ◽  
Gene Set Enrichment Analysis ◽  
Gene Set ◽  
Gene Sets

Aim and Objective: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, “repositioning” of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures. Materials and Methods: First, a “gene set–compound” network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A “cancer–functional gene set– compound” network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained. Results: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment. Conclusion: Our method can effectively identify compounds with a potential to be “repositioned” for cancer treatment according to their active mechanisms and their association with patients’ survival time.

Independent validation of simbiosys tumorscope to predict response to neoadjuvant chemotherapy (NACT) in early breast cancer (EBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 582-582
Author(s):  
Gong He ◽  
Frederick Howard ◽  
Tushar Pandey ◽  
Hiroyuki Abe ◽  
Rita Nanda
Keyword(s):  
Breast Cancer ◽  
Sensitivity And Specificity ◽  
Cancer Biology ◽  
Tumor Volume ◽  
Performance Metrics ◽  
External Validation ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Biophysical Model ◽  
Lymph Node Status

582 Background: Despite substantial advances in the understanding of breast cancer biology, the decision to use NACT for EBC is based on tumor size, lymph node status, and subtype. Even with aggressive therapy, the majority of women will not achieve a pathologic complete response (pCR). Investigational treatment regimens, including immunotherapy, can increase pCR rates, but are associated with irreversible immune-related toxicities. Being able to accurately predict pCR could identify candidates for intensification or de-escalation of NACT, allowing for personalized medicine. SimBioSys TumorScope (TS) is a biophysical model that utilizes baseline MRI, receptor status, and planned treatment regimen to simulate response to NACT over time. TS has demonstrated accurate prediction of pCR in prior studies. Here, we describe an independent external validation of TS. Methods: We conducted a retrospective study of University of Chicago patients (pts) who received NACT for EBC from Jan 2010 - March 2020. Pts must have had a pretreatment breast MRI. Tumors were analyzed using TS by investigators who were blinded to response data. TS predicted pCR was predefined as a residual tumor volume < 0.01 cm3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. Results: 144 tumors from 141 pts were analyzed. Average age was 52 yrs; 65% had stage II and 19% had stage III disease. Sensitivity and specificity of TS for predicting pCR were 90.4% and 92.4%, respectively. Of the 7 patients who were predicted to achieve a pCR but did not, 5 had a tumor cellularity < 5%. With a median follow-up of 4.7 yrs, the 4-yr distant disease free survival (DDFS) was 100% for patients predicted to achieve pCR, versus 81.5% for those predicted to have residual disease. Results were generally robust for all subgroups analyzed (Table). Conclusions: TS accurately predicts pCR and DDFS from baseline MRI and clinicopathologic data. Given the high sensitivity and specificity of this assay across breast cancer subtypes, TS can be used to aid in escalation/de-escalation strategies for EBC.[Table: see text]

scholarly journals M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Masanori Oshi ◽  
Yoshihisa Tokumaru ◽  
Mariko Asaoka ◽  
Li Yan ◽  
Vikas Satyananda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Biology ◽  
Clinical Characteristics ◽  
Critical Role ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
M1 Macrophage ◽  
Tumor Immune Microenvironment ◽  
Cell Cycle Related Gene ◽  
High Level

Abstract Tumor associated macrophages (TAMs) play a critical role in biology of various cancers, including breast cancer. In the current study, we defined “M1” macrophage and “M1”/“M2” ratio by transcriptomic signatures using xCell. We investigated the association between high level of “M1” macrophage or “M1”/“M2” ratio and the tumor immune microenvironment by analyzing the transcriptome of publicly available cohorts, TCGA and METABRIC. We found that “M1” high tumors were not associated with prolonged survival compared with “M1” low tumors, or with the response to neoadjuvant chemotherapy. “M1” high tumors were associated with clinically aggressive features and “M1” high tumors enriched the cell proliferation and cell cycle related gene sets in GSEA. At the same time, “M1” high tumors were associated with high immune activity and favorable tumor immune microenvironment, as well as high expression of immune check point molecules. Strikingly, all these results were mirrored in “M1”/“M2” ratio high tumors. In conclusion, transcriptomically defined “M1” or “M1”/“M2” high tumors were associated with aggressive cancer biology and favorable tumor immune microenvironment but not with survival benefit, which resembled only part of their conventional clinical characteristics.

Tamoxifen therapy in primary breast cancer: biology, efficacy, and side effects.

1989 ◽  
Vol 7 (6) ◽  
pp. 803-815 ◽  
Author(s):  
R R Love
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Primary Breast Cancer ◽  
Cancer Biology ◽  
Biological Effects ◽  
Disease Free Survival ◽  
Free Survival ◽  
Beneficial Effects ◽  
Tamoxifen Citrate ◽  
Disease Free

Since its introduction into clinical use in the early 1970s, the synthetic antiestrogen tamoxifen citrate has been shown to contribute to the control of human breast cancer in increasingly significant ways. While its mechanisms of action and pharmacology are incompletely understood, tamoxifen appears to act predominantly by blocking the action of estrogen by binding to the estrogen receptor. Clinical trials of tamoxifen for 1 to 2 years in primary breast cancer demonstrate consistent beneficial effects on disease-free survival, but only suggested beneficial effects on survival. Routine use of adjuvant tamoxifen for 5 years or more will depend on the results of ongoing large clinical trials of efficacy and detailed studies of unknown biological effects on other tissues.

scholarly journals ALDH1 Expression and Vasculogenic Mimicry Are Positively Associated with Poor Prognosis in Patients with Breast Cancer

2018 ◽  
Vol 49 (3) ◽  
pp. 961-970 ◽  
Author(s):  
Peng Xing ◽  
Huiting Dong ◽  
Qun Liu ◽  
Tingting Zhao ◽  
Fan Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cox Regression ◽  
Histological Grade ◽  
Vasculogenic Mimicry ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Double Positive ◽  
The Status ◽  
Aldh1 Expression

Background/Aims: This study aimed to explore the prognostic value of aldehyde dehydrogenase 1 (ALDH1) expression and vasculogenic mimicry (VM) in patients with breast cancer. Methods: ALDH1 expression and the presence of VM were examined by immunohistochemistry and CD31/PAS double staining, respectively, using formalin-fixed paraffin-embedded tissues from 202 breast cancer patients. The mean follow-up period ranged from 15 to 115 months. The Kaplan-Meier method was used to plot survival curves. Prognostic values were assessed by multivariate analysis using the Cox regression model. Results: ALDH1 expression was strongly associated with VM (P = 0.005). ALDH1 expression was positively correlated with histological grade (P = 0.011). Both ALDH1 expression and VM were negatively related to the status of the estrogen receptor and progesterone receptor and were statistically increased in triple-negative breast cancer. Patients with ALDH1 expression or VM displayed poorer disease-free survival (DFS) and overall survival (OS) than ALDH1-negative or VM-negative patients, with the worst OS and DFS observed in ALDH1/VM-double-positive patients. ALDH1-positive and VM-positive were independent survival risk factors for DFS and OS. Conclusion: ALDH1 expression and VM are correlated with the survival rate of patients with breast cancer. ALDH1 and VM, either alone or together, are prognostic factors in patients with breast cancer.

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