scholarly journals Genomic Features of Rapid Versus Late Relapse in Triple Negative Breast Cancer 

2021 ◽  
Author(s):  
Yiqing Zhang ◽  
Sarah Asad ◽  
Zachary Weber ◽  
David Tallman ◽  
William Nock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Late Relapse ◽  
Primary Tumors ◽  
Genomic Features ◽  
Immune Signatures ◽  
M1 Macrophage

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors.Methods: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; relapse/death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; >2 years) or ‘no relapse’ (nrTNBC: >5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n=453), and whole genome copy number and mutation data for 171 cancer-related genes (n=317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features.Results: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n=63 patients), testing (n=63) and independent validation (n=34) cohorts, although performance of all models were overall modest. Conclusions: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

scholarly journals Genomic features of rapid versus late relapse in triple negative breast cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yiqing Zhang ◽  
Sarah Asad ◽  
Zachary Weber ◽  
David Tallman ◽  
William Nock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Late Relapse ◽  
Primary Tumors ◽  
Genomic Features ◽  
Immune Signatures ◽  
M1 Macrophage

Abstract Background Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; > 2 years) or ‘no relapse’ (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. Results Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. Conclusions We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

scholarly journals Abundance of Regulatory T Cell (Treg) as a Predictive Biomarker for Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3038 ◽  
Author(s):  
Masanori Oshi ◽  
Mariko Asaoka ◽  
Yoshihisa Tokumaru ◽  
Fernando A. Angarita ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Biomarker ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Cancer Aggressiveness

Regulatory CD4+ T cell (Treg), a subset of tumor-infiltrating lymphocytes (TILs), are known to suppress anticancer immunity but its clinical relevance in human breast cancer remains unclear. In this study, we estimated the relative abundance of Tregs in breast cancer of multiple patient cohorts by using the xCell algorithm on bulk tumor gene expression data. In total, 5177 breast cancer patients from five independent cohorts (TCGA-BRCA, GSE96058, GSE25066, GSE20194, and GSE110590) were analyzed. Treg abundance was not associated with cancer aggressiveness, patient survival, or immune activity markers, but it was lower in metastatic tumors when compared to matched primary tumors. Treg was associated with a high mutation rate of TP53 genes and copy number mutations as well as with increased tumor infiltration of M2 macrophages and decreased infiltration of T helper type 1 (Th1) cells. Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) was significantly associated with low Treg abundance in triple negative breast cancer (TNBC) but not in ER-positive/Her2-negative subtype. High Treg abundance was significantly associated with high tumor expression of multiple immune checkpoint inhibitor genes. In conclusion, Treg abundance may have potential as a predictive biomarker of pCR after NAC in TNBC.

scholarly journals Machine learning predicts rapid relapse of triple negative breast cancer

2019 ◽  
Author(s):  
Yiqing Zhang ◽  
William Nock ◽  
Meghan Wyse ◽  
Zachary Weber ◽  
Elizabeth Adams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Machine Learning ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Support Vector ◽  
Chi Square ◽  
Genomic Features ◽  
Immune Signatures ◽  
Metastatic Relapse ◽  
Significant Difference

ABSTRACTPurposeMetastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagnosis is associated with particularly aggressive disease and a distinct clinical course relative to TNBCs that relapse beyond 2 years. We hypothesized that rapid relapse TNBCs (rrTNBC; metastatic relapse or death <2 years) reflect unique genomic features relative to late relapse (lrTNBC; >2 years).Patients and MethodsWe identified 453 primary TNBCs from three publicly-available datasets and characterized each as rrTNBc, lrTNBC, or ‘no relapse’ (nrTNBC: no relapse/death with at least 5 years follow-up). We compiled primary tumor clinical and multi-omic data, including transcriptome (n=453), copy number alterations (CNAs; n=317), and mutations in 171 cancer-related genes (n=317), then calculated published gene expression and immune signatures.ResultsPatients with rrTNBC were higher stage at diagnosis (Chi-square p<0.0001) while lrTNBC were more likely to be non-basal PAM50 subtype (Chi-square p=0.03). Among 125 expression signatures, five immune signatures were significantly higher in nrTNBCs while lrTNBC were enriched for eight estrogen/luminal signatures (all FDR p<0.05). There was no significant difference in tumor mutation burden or percent genome altered across the groups. Among mutations, onlyTP53mutations were significantly more frequent in rrTNBC compared to lrTNBC (Fisher exact FDR p=0.009). To develop an optimal classifier, we used 77 significant clinical and ‘omic features to evaluate six modeling approaches encompassing simple, machine learning, and artificial neural network (ANN). Support vector machine outperformed other models with average receiver-operator characteristic area under curve >0.75.ConclusionsWe provide a new approach to define TNBCs based on timing of relapse. We identify distinct clinical and genomic features that can be incorporated into machine learning models to predict rapid relapse of TNBC.

scholarly journals Pilose antler polypeptides promote chemosensitization and T-cell infiltration of triple-negative breast cancer

2021 ◽  
Vol 85 ◽  
pp. 104664
Author(s):  
Mohan Li ◽  
Kexin Zheng ◽  
Shiliang Ma ◽  
Pengpeng Hu ◽  
Bo Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Infiltration ◽  
T Cell Infiltration

The exosomes derived from CAR-T cell efficiently target mesothelin and reduce triple-negative breast cancer growth

2021 ◽  
Vol 360 ◽  
pp. 104262
Author(s):  
Pengxiang Yang ◽  
Xingjian Cao ◽  
Huilong Cai ◽  
Panfeng Feng ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Growth ◽  
Car T Cell ◽  
Car T ◽  
Breast Cancer Growth

scholarly journals CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer

Oncotarget ◽  
2015 ◽  
Vol 6 (28) ◽  
pp. 25356-25367 ◽  
Author(s):  
Claudia Paret ◽  
Petra Simon ◽  
Kirsten Vormbrock ◽  
Christian Bender ◽  
Anne Kölsch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative

scholarly journals DNAJC28 expression associates with survival in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Microarray Data ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of DnaJ (Hsp40) homolog, subfamily C, member 28, encoded by DNAJC28 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, DNAJC28 expression was correlated with overall survival in patients with breast cancer. DNAJC28 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

scholarly journals 614 Investigating immune mediated mechanisms of PARPi resistance in BRCA1-associated triple negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
Anita Mehta ◽  
Madeline Townsend ◽  
Madisson Oliwa ◽  
Patrice Lee ◽  
Nicholas Saccomano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Triple Combination ◽  
Tumor Clearance ◽  
Sting Pathway

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi) have improved the outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. Our preclinical studies demonstrated that PARPi activates the cGAS/STING pathway and recruitment of anti-tumor CD8+ T-cells that are required for tumor clearance [1]. These studies contributed to development of clinical trials testing PARPi plus immune checkpoint blockade (ICB). Unfortunately, early phase trials of PARPi + ICB have not yet suggested efficacy will be superior to PARPi monotherapy. Lack of demonstrated clinical synergy between PARPi + ICB underscores the need to study the tumor microenvironment (TME) during PARPi therapy to identify optimal strategies to enhance T-cell activation. We recently showed that PARPi induces CSF-1R+ suppressive tumor associated macrophages (TAMs) that restrict antitumor immune responses, contributing to PARPi resistance [2]. Removing TAMs with anti-CSF-1R therapy in combination with PARPi significantly enhanced overall survival (OS) compared to PARPi monotherapy in preclinical models [2]. Here, we investigate how modulating TAMs can enhance PARPi + ICB.MethodsMice bearing BRCA1-deficient TNBC (K14-Cre;Brca1f/f;p53f/f) tumors were treated for 98 days with PARPi (Talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and then followed for survival. Flow cytometry was employed to elucidate changes in the TME after treatment.ResultsPARPi conferred a significant survival advantage over vehicle treated mice (median OS 33 v. 14 days; p=0.0034) and 2/8 PARPi-treated mice experienced complete tumor clearance at day 98. PARPi + CSF-1Ri treated mice (median OS 140 days) remarkably cleared 7/10 tumors by day 98. The addition of anti-PD-1 to PARPi did not enhance OS compared to PARPi monotherapy. The triple combination of anti-PD-1 + PARPi + CSF-1Ri has not yet significantly enhanced the median OS compared to PARPi + CSF-1Ri (ongoing; 168 v. 140 days); nor did it increase clearance of tumor by day 98 (7/10). However, the triple combination led to superior long term tumor clearance. At day 161 the triple combination exhibited 5/10 tumor free mice compared to 2/10 treated with PARPi + CSF-1Ri. To elucidate how CSR-1Ri enhanced PARPi + ICB responses, flow cytometry was performed and revealed increased expression of the co-stimulatory molecule CD80, reduced tissue resident macrophages (CX3CR1+) and lower CSF-1R expression compared to PARPi + ICB.ConclusionsThese data suggest that targeting immunosuppressive macrophages may induce a favorable anti-tumor immune response and enhance responses to PARPi plus ICB. We are currently evaluating the adaptive immune response in this context.ReferencesPantelidou, C., et al., PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discovery, 2019: p. CD-18-1218.Mehta, A.K., et al., Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2021. 2(1): p. 66–82.

scholarly journals Differential expression of cyclin A2 in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Differential Expression ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Ductal Cells ◽  
Cyclin A2

Women diagnosed with triple negative breast cancer can benefit neither from endocrine therapy nor from HER2-targeted therapies (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding cyclin A2, CCNA2, when comparing the tumor cells of patients with triple negative breast cancer to normal mammary ductal cells (2). CCNA2 was also differentially expressed in bulk tumor in human breast cancer (3). CCNA2 mRNA was present at significantly increased quantities in TNBC tumor cells relative to normal mammary ductal cells. Analysis of human survival data revealed that expression of CCNA2 in primary tumors of the breast was correlated with overall survival in patients with basal-like type cancer, while within triple negative breast cancer, primary tumor expression of CCNA2 was correlated with overall survival in patients with basal-like 1, basal-like 2, and mesenchymal subtype disease. CCNA2 may be of relevance to initiation, maintenance or progression of triple negative breast cancers.

Sign in / Sign up

Export Citation Format

Share Document