Triple-negative breast cancer: challenges and treatment options

TNBCs or Triple negative breast cancers are characterized by the deficiency of progesterone and estrogen receptors and also the absence down regulation of Human epithelial growth receptor type 2 (HER2). TNBCs have low prognosis rate because of heterogeneity.The heterogeneous nature of this cancer has constrained the effective progress in drug targeting among certain people.. In general HER2, PR and ER and the rate of proliferation are main predictive and prognostic factors in the detection of cancer of breast.Several pathways are involved in the progression of triple negative breast cancer from basal like cancer cells. The foremost being the loss by BRCA1-mediated pathway or mutation in the expression of several receptors.Certain groups have made some progress in unwinding TNBC's biological diversity and relating patterns of gene expression to molecular or genotypic subtypes.Earlier molecular categories of breast cancer use PAM50 via gene expression analysis to separate the breast cancer into the 4 intrinsic subtypes classified among many TNBCs in basal (BL) group and others divided between HER2 and luminal rich group. Currently, targeted therapy for TNBCs has not been approved. Nonetheless, a continuous progress has been made to detect the tumors at specific site for targeting and establish novel improved therapy.This review speaks about different approaches to TNBC treatment like cytotoxic therapy, targeted strategies, and chemotherapeutics by damage to DNA and targeting for repair of DNA and potent Nano carriers for targeting TNBC.

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Genotypic characterization of phenotypically defined triple-negative breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.500 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 500-500 ◽

Cited By ~ 3

Author(s):

J. A. Sparano ◽

L. J. Goldestin ◽

B. H. Childs ◽

S. Shak ◽

S. Badve ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Triple Negative Breast Cancer ◽

Intracellular Signaling ◽

Triple Negative ◽

Phenotypic Characterization ◽

Breast Cancers ◽

Nucleosome Assembly ◽

Expression Of Genes ◽

Cancer Phenotypes

500 Background: Triple negative breast cancer (TNBC) is associated with a higher risk of recurrence and earlier recurrences than other breast cancer phenotypes. We evaluated the genotypic features of TNBC compared with hormone receptor (HR)-positive disease, and also evaluated genotypic features associated with recurrence. Methods: RNA extracted from tumor samples obtained from 764 patients with stage I-III breast cancer was analyzed by RT-PCR for 371 genes. All patients received adjuvant chemotherapy (plus hormonal therapy in HR-positive disease) in trial E2197; HR and HER2 expression were evaluated by immunohistochemistry (IHC) in a central lab (J Clin Oncol 26:2473–2481). An unsupervised clustering analysis was performed in all samples (N=764). Cox proportional hazard models were used to identify differences in gene expression in TNBC versus HR-positive disease, and with recurrence in phenotypically defined (by IHC) TNBC (N=246) and HR-positive (N=465) disease. Results: Unsupervised analysis revealed two major clusters that differed with regard to HR expression by IHC. Supervised analysis comparing the TNBC vs. HR-positive phenotypes revealed 269 genes (73%) with significantly different expression (p<0.0001). The top 10% of genes exhibiting higher expression the TN group included genes associated with nucleosome assembly (CENPA), kinase activity (TTK), cell division (KIFC2), proliferation (BUB1), intracellular signaling (DEPDC1), DNA repair (CHK1), anti-apoptosis (GSTP1), and transcriptional regulation (MYBL2). There was increased expression of genes for which inhibitors are currently being evaluated, including AURKB and CHK1 in TNBC, and IGF1R and RhoC in HR-positive disease. Although GRB7 expression was significantly lower in the TN group, increased expression of GRB7 was the only gene in the TNBC group (but not the HR-positive group) associated with increased recurrence (p=0.04), and did not correlate with nodal status, tumor size, or grade. Conclusions: We genotypically characterized breast cancers that have also undergone rigorous phenotypic characterization.. There were significant differences in gene expression between the TN and HR-positive groups, including genes for which targeted agents are currently being evaluated in the clinic. [Table: see text]

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A paclitaxel and microRNA-124 coloaded stepped cleavable nanosystem against triple negative breast cancer

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00800-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Chuanrong Chen ◽

Ming Shen ◽

Hongze Liao ◽

Qianqian Guo ◽

Hao Fu ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Disulfide Bonds ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Treatment Options ◽

Breast Cancers ◽

Mesenchymal Transition ◽

Tumour Metastasis ◽

Microrna 124

Abstract Background Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. Therefore, studies aiming to explore new therapeutic strategies for advanced TNBC are urgently needed. According to recent studies, microRNA-124 (miR124) not only inhibits tumour growth but also increases the sensitivity of TNBC to paclitaxel (PTX), suggesting that a platform combining PTX and miR124 may be an advanced solution for TNBC. Results Herein, we constructed a stepped cleavable calcium phosphate composite lipid nanosystem (CaP/LNS) to codeliver PTX and miR124 (PTX/miR124-NP). PTX/miR124-NP exhibited superior tumor microenvironment responsive ability, in which the surface PEG layer was shed in the mildly acidic environment of tumor tissues and exposed oligomeric hyaluronic acid (o-HA) facilitated the cellular uptake of CaP/LNS by targeting the CD44 receptor on the surface of tumor cells. Inside tumour cells, o-HA detached from CaP/LNS due to the reduction of disulfide bonds by glutathione (GSH) and inhibited tumour metastasis. Then, PTX and miR124 were sequentially released from CaP/LNS and exerted synergistic antitumour effects by reversing the Epithelial-Mesenchymal Transition (EMT) process in MDA-MB-231 cells. Moreover, PTX/miR124-NP showed significant antitumour efficiency and excellent safety in mice bearing MDA-MB-231 tumours. Conclusion Based on these results, the codelivery of PTX and miR124 by the CaP/LNS nanosystem might be a promising therapeutic strategy for TNBC.

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Current and emerging treatment options in triple-negative breast cancer

Oncology Reviews ◽

10.4081/oncol.2010.5 ◽

2011 ◽

Vol 4 (1) ◽

pp. 5

Author(s):

Omer Dizdar ◽

Kadri Altundag

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Treatment Options ◽

Growth Factor Receptor ◽

Immunohistochemical Analysis ◽

Endocrine Treatment ◽

Breast Cancers ◽

Chemotherapy Drugs

Triple-negative breast cancer is defined by the lack of estrogen receptor, progesterone receptor and HER2 expression with immunohistochemical analysis. Triplenegative breast cancers are poorly differentiated, characterized by high histological grade and occur at a younger age. Treatment options are limited as these tumors are naturally resistant to existing targeted therapies, i.e., endocrine treatment and trastuzumab. An improved understanding of the biology of TNBC has led to evaluation of DNA-damaging chemotherapy drugs and targeted agents, including poly (ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, etc., in the treatment of TNBC. This review focuses on outlining the current and emerging treatment options in patients with triple-negative breast cancer.

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Optical Redox Imaging Differentiates Triple-Negative Breast Cancer Subtypes

Advances in Experimental Medicine and Biology - Oxygen Transport to Tissue XLII ◽

10.1007/978-3-030-48238-1_40 ◽

2021 ◽

pp. 253-258

Author(s):

Jinxia Jiang ◽

Min Feng ◽

Annemarie Jacob ◽

Lin Z. Li ◽

He N. Xu

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Response Patterns ◽

Breast Cancers ◽

Cancer Subtypes ◽

Mitochondrial Inhibitors ◽

Tnbc Cell

AbstractTriple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells differ from each other in many ways such as gene expression, metabolic activity, tumorigenicity, and invasiveness. Recently, many research and clinical efforts have focused on metabolically targeted therapy for TNBC. Metabolic characterization of TNBC cell lines can facilitate the assessment of therapeutic effects and assist in metabolic drug development. Herein, we used optical redox imaging (ORI) techniques to characterize TNBC subtypes metabolically. We found that various TNBC cell lines had differing redox statuses (levels of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavin adenine dinucleotide (FAD), and the redox ratio (FAD/(NADH+FAD)). We then metabolically perturbed the cells with mitochondrial inhibitors and an uncoupler and performed ORI accordingly. As expected, we observed that these TNBC cell lines had similar response patterns to the metabolic perturbations. However, they exhibited differing redox plasticity. These results suggest that subtypes of TNBC cells are different metabolically and that ORI can serve as a sensitive technique for the metabolic profiling of TNBC cells.

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MYBL1 Knockdown in a Triple Negative Breast Cancer Line: Evidence of Down-Regulation of MYBL2, TCF19 and KIF18b Expression

Austin Journal of Cancer and Clinical Research ◽

10.26420/austinjcancerclinres.2021.1090 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Player A ◽

◽

Abraham N ◽

Abdulrahman N ◽

Nsende E ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Cell Line ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Gene Expression Omnibus ◽

Breast Cancers ◽

Down Regulation ◽

Cell Cycle Signaling

Purpose: The MYBL1 gene is a strong transcriptional activator, associated with cell cycle signaling and differentiation. Data show the gene is overexpressed in triple negative breast cancers. Considering the possibility that MYBL1 might be involved in events associated with the pathogenesis of these cancers, we sought to identify genes associated with MYBL1 expression in triple negative breast cancer. Methods: shRNA lentiviral knockdown was used to down-regulate the MYBL1 gene. Microarray analyses were used to identify genes either directly or indirectly affected by targeting MYBL1 knockdown. Data analyses was performed utilizing Affymetrix TAC 4.0, Chip X transcription factor analyses, Target Scan miRNA analyses, and STRING analyses was used to determine protein: protein interaction and pathway analyses. Web Gestalt and Gene Ontology were used to determine pathway and gene-set enrichments. Publicly available patient and cell line datasets were retrieved and processed using resources available in Gene Expression Omnibus and Oncomine. The polymerase chain reaction and western analyses were used to determine transcript and protein levels, respectively. Results: Knockdown of MYBL1 in a triple negative breast cell line led to down-regulation of MYBL2, TCF19, KIF18b along with an enrichment of cell cycle signaling genes. Gene expression analyses show that MYBL1, MYBL2, TCF19 and KIF18b display a similar pattern of expression in breast cell lines and many of the archival patient datasets examined. Conclusion: TNBC is a heterogeneous subtype, so these data suggest that cancers that over-express MYBL1, express MYBL2, TCF19 and KIF18b. Bioinformatic analyses suggest MYBL1 regulates MYBL2 which leads to regulation of TCF19 and KIF18b.

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Triple Negative Breast Cancer Pathologic Diagnosis and Current Chemotherapy Treatment Options

European Oncology & Haematology ◽

10.17925/eoh.2014.10.1.35 ◽

2014 ◽

Vol 10 (01) ◽

pp. 35 ◽

Cited By ~ 3

Author(s):

Bernardo L Rapoport ◽

Simon Nayler ◽

Georgia S Demetriou ◽

Shun D Moodley ◽

Carol A Benn ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Hormone Receptors ◽

Triple Negative ◽

Treatment Options ◽

Single Agent ◽

Metastatic Breast ◽

Complete Response ◽

Breast Cancers ◽

Metastatic Setting

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumours, both clinically and pathologically. These cancers are characterised by the lack of expression of the hormone receptors oestrogen receptor (OR) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomised trials. Numerous studies have now shown that TNBC has significantly higher pathological complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathological diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant and metastatic setting, including an assessment of future directions of treatment.

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Response to Vemurafenib in Metastatic Triple-Negative Breast Cancer Harbouring a BRAF V600E Mutation: A Case Report and Electronically Captured Patient-Reported Outcome

Case Reports in Oncology ◽

10.1159/000513905 ◽

2021 ◽

pp. 616-621

Author(s):

Magdalena Pircher ◽

Thomas Winder ◽

Andreas Trojan

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Braf Inhibitor ◽

Local Therapy ◽

Braf V600e Mutation ◽

Braf V600e ◽

Breast Cancers ◽

Patient Reported

Effective treatment options are still scarce for metastatic triple-negative breast cancers. An increasing interest in the mutational landscape of this disease will facilitate novel therapeutic strategies in a variety of cancers. Here we report the case of a 38-year-old female patient who developed multiple lung metastasis of a triple-negative breast cancer 2 years after the completion of local therapy. When she progressed after two palliative chemotherapy lines and local electroporation, a next-generation sequencing revealed a BRAF V600E mutation for which we initiated therapy with the BRAF inhibitor vemurafenib. Radiological improvement was already evident after 3 months and has been ongoing for 19 months so far with very few side effects, as is demonstrated by electronically captured patient-reported outcomes. To our knowledge, this is the first published case where a BRAF V600E-mutated advanced triple-negative breast cancer was successfully treated with vemurafenib.

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Current and emerging treatment options in triple-negative breast cancer

Oncology Reviews ◽

10.4081/oncol.2010.43 ◽

2011 ◽

pp. 5-13

Author(s):

Omer Dizdar ◽

Kadri Altundag

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Treatment Options ◽

Growth Factor Receptor ◽

Immunohistochemical Analysis ◽

Endocrine Treatment ◽

Breast Cancers ◽

Chemotherapy Drugs

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Patient-derived triple negative breast cancer organoids provide robust model systems that recapitulate tumor intrinsic characteristics

10.1101/2021.08.09.455691 ◽

2021 ◽

Author(s):

Sonam Bhatia ◽

Melissa Kramer ◽

Suzanne Russo ◽

Payal Naik ◽

Gayatri Arun ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Cancer Biology ◽

Triple Negative ◽

Treatment Options ◽

Cell Types ◽

Model Systems ◽

Breast Cancers ◽

Robust Model

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, and an unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDOs) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBCs). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, our study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and better treatment options.

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NFKBIA deletion in triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.1012 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 1012-1012 ◽

Cited By ~ 2

Author(s):

Markus Bredel ◽

Hyunsoo Kim ◽

Nanda K. Thudi ◽

Denise M. Scholtens ◽

James A. Bonner ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Target Genes ◽

Triple Negative ◽

Lung Metastases ◽

Treatment Options ◽

Underlying Mechanism ◽

Breast Cancers ◽

Suppressor Activity ◽

Free Survival

1012 Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed >5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.

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