scholarly journals A New Gene Expression Signature for Triple-Negative Breast Cancer using Frozen Fresh Tissue before Neoadjuvant chemotherapy

2017 ◽  
Vol 23 (1) ◽  
pp. 101-111 ◽  
Author(s):  
Sandra K. Santuario-Facio ◽  
Servando Cardona-Huerta ◽  
Yadira X. Perez-Paramo ◽  
Victor Trevino ◽  
Francisco Hernandez-Cabrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Gene Expression Signature ◽  
Fresh Tissue ◽  
Expression Signature ◽  
New Gene

scholarly journals A Minimal lncRNA-mRNA Signature Predicts Sensitivity to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

2018 ◽  
Vol 48 (6) ◽  
pp. 2539-2548 ◽  
Author(s):  
Qian Wang ◽  
Chunmei Li ◽  
Peipei Tang ◽  
Runyuan Ji ◽  
Song Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Noncoding Rna ◽  
Triple Negative ◽  
Characteristic Curve ◽  
Gene Expression Signature ◽  
Receiver Operator Characteristic Curve ◽  
Response Score

Background/Aims: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that responds in a diverse manner to neoadjuvant chemotherapy (NAC). This study was aimed to uncover an RNA signature in TNBC patients which predicts pathological complete responses (pCR) to NAC by analyzing long noncoding RNA (lncRNA) and coding gene expression. Methods: Microarray datasets from 26 TNBC patients receiving NAC including ten patients showing pCR were obtained from the Gene Expression Omnibus database. Results: A total of 172 coding genes and 84 lncRNAs were differentially expressed between patients achieving pCR and those who did not. Filtering based on the predictive efficacy of response to NAC using receiver operator characteristic curve (ROC) and area under the curve (AUC) shortlisted 23 lncRNAs and 15 coding genes from consideration. Finally, a response score consisting of 1 lncRNA and 2 coding genes was developed: response score = 2.595*BPESC1 – 1.09*WDR72 –1.428*GADD45A – 0.731. The response score had good predictive performance (AUC=0.931, p< 0.01) and at the cut-off of 0.545, the response score had sensitivity and specificity of 0.8 and 0.9, respectively. Conclusion: We propose a simple gene expression signature of only three RNA species could be employed clinically to predict pCR in TNBC patients receiving NAC.

A gene expression signature of MEK pathway activation to predict survival in triple-negative breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1024-1024 ◽  
Author(s):  
Justin M. Balko ◽  
Melinda Sanders ◽  
Maria Gabriela Kuba ◽  
Joseph A. Pinto ◽  
Franco F. Doimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Gene Expression Signature ◽  
Expression Signature ◽  
Node Status ◽  
Pathway Activation

1024 Background: Tumor cell proliferation measured by Ki67 in the surgically removed tumor after neoadjuvant chemotherapy (NAC) has been shown to predict patient outcome in breast cancer. It is unclear from these studies if breast cancer subtype may account in part for the predictive ability of Ki67. Thus, we tested whether Ki67 score in the surgically-resected residual tumor (RT) after NAC predicted outcome in a cohort of triple negative breast cancer (TNBC). Gene expression profiling was performed to identify molecular subtype and test the association with gene modules indicative of signaling pathway activation. Methods: Ki67 was scored in the RT of 89 patients with stage II-III TNBC (ER/PR/HER2 negative by IHC at diagnosis) that had been treated with NAC. Expression levels for 450 genes were quantified by Nanostring. Ki67, node and menopause status, age, therapy type (± taxanes), molecular subtype, and gene expression scores were tested for association to RFS and OS using univariate and multivariate CoxPH models. Results: Ki67 score in the post-NAC RT demonstrated a wide range (1.5-77.7%; median: 36.2%). Twenty seven % of RTs were 3+ HER2 by IHC. Molecular subtype in the RT was as follows: 64% Basal-like; 20% HER2-enriched; 6% LumA; 6% LumB; 4% Normal-like. In univariate analyses to respectively predict RFS and OS, node status (p=0.005 and p=0.02), number of nodes (p=0.003 and p<0.001), and the score of a gene expression module of MEK pathway activation (p=0.04 and p=0.01,) were significant. Basal-like subtype approached significance for RFS (p=0.1) and OS (p=0.05). In multivariate analyses, node status (p=0.002 for RFS and p<0.001 for OS) and MEK pathway activation score (p=0.04 and p=0.01) were significant predictors. Conclusions: Ki67 in the RT after NAC was not predictive of outcome in a cohort of TNBC. However, a gene expression signature of activated MEK was negatively associated with outcome. These data are consistent with the reported preclinical activity of MEK inhibitors against basal-like breast cancer cells and a possible role of this signaling pathway in chemotherapy resistance. They also support deep sequencing studies to identify genetic alterations in the RAS/MEK/MAPK pathway in TNBC.

scholarly journals Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer

2021 ◽  
Author(s):  
Sung Gwe Ahn ◽  
Seon-Kyu Kim ◽  
Jonathan H. Shepherd ◽  
Yoon Jin Cha ◽  
Soong June Bae ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Pathologic Complete Response ◽  
Gene Expression Signature ◽  
Complete Response ◽  
Gene Signature ◽  
Expression Signature

Abstract Purpose The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). We strove to understand the biological, genomic, and clinical characteristics associated with SP142 PD-L1 positivity in TNBC patients. Methods Using 149 TNBC formalin-fixed paraffin-embedded tumor samples, tissue microarray (TMA) and gene expression microarrays were performed in parallel. The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides. We next generated a gene signature reflective of SP142 status and evaluated signature distribution according to TNBCtype and PAM50 subtypes. A SP142 gene expression signature was identified and was biologically and clinically evaluated on the TNBCs of TCGA, other cohorts, and on other malignancies treated with immune checkpoint inhibitors (ICI). Results Using SP142, 28.9% of samples were PD-L1 protein positive. The SP142 PD-L1-positive TNBC had higher CD8+ T cell percentage, stromal tumor-infiltrating lymphocyte levels, and higher rate of the immunomodulatory TNBCtype compared to PD-L1-negative samples. The recurrence-free survival was prolonged in PD-L1-positive TNBC. The SP142-guided gene expression signature consisted of 94 immune-related genes. The SP142 signature was associated with a higher pathologic complete response rate and better survival in multiple TNBC cohorts. In the TNBC of TCGA, this signature was correlated with lymphocyte-infiltrating signature scores, but not with tumor mutational burden or total neoantigen count. In other malignancies treated with ICIs, the SP142 genomic signature was associated with improved response and survival. Conclusions We provide multi-faceted evidence that SP142 PDL1-positive TNBC have immuno-genomic features characterized as highly lymphocyte-infiltrated and a relatively favorable survival.

scholarly journals Interferon-beta represses cancer stem cell properties in triple-negative breast cancer

2017 ◽  
Vol 114 (52) ◽  
pp. 13792-13797 ◽  
Author(s):  
Mary R. Doherty ◽  
HyeonJoo Cheon ◽  
Damian J. Junk ◽  
Shaveta Vinayak ◽  
Vinay Varadan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Mammary Epithelial Cells ◽  
Gene Expression Signature ◽  
Tumor Infiltrating Lymphocytes ◽  
Gene Signature ◽  
Mesenchymal Transition

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non–CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

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