scholarly journals Therapeutic Strategies for Metastatic Triple-Negative Breast Cancers: From Negative to Positive

2021 ◽  
Vol 14 (5) ◽  
pp. 455
Author(s):  
Dey Nandini ◽  
Aske Jennifer ◽  
De Pradip
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Complex Form ◽  
High Rate ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Poor Overall Survival ◽  
Term Survival

Metastatic triple-negative breast cancer (TNBC) is a distinct and immensely complex form of breast cancer. Among all subtypes of breast cancers, TNBC has a comparatively high rate of relapse, a high rate of distant metastasis, and poor overall survival after standard chemotherapy. Chemotherapy regimens are an essential component of the management of this estrogen receptor-negative, progesterone receptor-negative, and epidermal growth factor receptor2 negative subtype of breast cancers. Chemotherapy is critical for preventing the recurrence of the disease and for achieving long-term survival. Currently, a couple of agents are approved for the management of this disease, including chemotherapy like eribulin, targeted therapy like PARP inhibitor, as well as an antibody-drug conjugate (ADC) to target TROP2. Like many other metastatic cancers, immune checkpoint inhibitors (ICIs) have also been approved for TNBC patients with PD-L1 positive tumors and high tumor mutational burden. In this review article, we discuss these newly approved and promising novel agents that may change the therapeutic landscape for advanced/metastatic TNBC patients.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Inflammatory breast cancer: Where are we now?

2003 ◽  
Vol 11 (3) ◽  
pp. 143-144
Author(s):  
Sladjana Filipovic
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Combined Modality Therapy ◽  
Survival Rates ◽  
Distant Metastases ◽  
Axillary Node ◽  
High Rate ◽  
Breast Cancers ◽  
Term Survival ◽  
Palpable Mass

Inflammatory breast cancer is perhaps the most aggressive form of breast neoplasm, with a poor prognosis. Clinically, inflammatory breast cancer is characterized by erythema and edema of the skin of the breast, called "peau d`orange", with or without an associated palpable mass. This form represents 1% to 6% (doubled during the past two decades) of all newly diagnosed breast malignancies and is often considered together with local advanced breast cancer, despite specific differential features. The reported 5-year survival rates range from 10% to 75%. On mammography, a diffuse increase in density and skin thickening may be present. Pathologic confirmation of invasion of dermal lymphatics by malignant cells can help distinguish this condition from benign mastitis. Most inflammatory breast cancers are on biopsy poorly differentiated ductal carcinomas, mainly estrogen and progesterone receptor negative. HER2/neu-overexpression and p53 gene mutations are frequently present. The probability of axillary node involvement is approximately 90%. Contralateral breast cancer develops in 25% to 50% of the patients, usually in the presence of metastases. Inflammatory breast cancer has a high rate of locoregional recurrence after surgery and/or radiotherapy and the rapid appearance of distant metastases. However, long-term survival is possible for these patients if treated with multimodality therapy including polychemotherapy, mastectomy, and loco-regional radiotherapy. The optimal sequencing of combined modality therapy has not been determined. Although not all patients are candidates for such a regimen (often due to progression during treatment), for those that complete all phases of therapy, more than one-third will be alive without disease at 10 years.

scholarly journals Mass Spectrometry-Based Omics for the Characterization of Triple-Negative Breast Cancer Bio-Signature

2020 ◽  
Vol 10 (4) ◽  
pp. 277
Author(s):  
Ioana-Ecaterina Pralea ◽  
Radu-Cristian Moldovan ◽  
Adrian-Bogdan Țigu ◽  
Corina Ionescu ◽  
Cristina-Adela Iuga
Keyword(s):  
Breast Cancer ◽  
Mass Spectrometry ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Biomarker Discovery ◽  
High Rate ◽  
Current Standard ◽  
Poor Overall Survival ◽  
Clinical Behavior

Triple-negative breast cancer (TNBC) represents an unmet medical need due to a high rate of metastatic occurrence and poor overall survival, pathology aggressiveness, heterogeneous clinical behavior and limited cytotoxic chemotherapy options available because of the absence of targetable receptors. The current standard of care in TNBC is represented by chemotherapy and surgery associated with low overall survival and high relapse rates. Hopes of overcoming current limited and unspecific approaches of TNBC therapy lie in studying the metabolic rewiring of these types of breast cancer, thus understanding the mechanisms involved in the occurrence and progression of the disease. Due to its heterogeneity, a clinically relevant sub-classification of this type of breast cancer based on biomarker panels is greatly needed in order to guide treatment decisions. Mass spectrometry-based omics may provide very useful tools to address the current needs of targetable biomarker discovery and validation. The present review aims to provide a comprehensive view of the current clinical diagnosis and therapy of TNBC highlighting the need for a new approach. Therefore, this paper offers a detailed mass spectrometry-based snapshot of TNBC metabolic adjustment, emphasizing a complex network of variables governing the diverse and aggressive clinical behavior of TNBC.

CD147 expression is associated with poor overall survival in chemotherapy treated triple-negative breast cancer

2018 ◽  
Vol 71 (11) ◽  
pp. 1007-1014 ◽  
Author(s):  
Ming Liu ◽  
Julia Y S Tsang ◽  
Michelle Lee ◽  
Yun-Bi Ni ◽  
Siu-Ki Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Resistance ◽  
Breast Cancers ◽  
Poor Overall Survival ◽  
Functional Roles ◽  
Cd147 Expression ◽  
Basal Like Breast Cancer

AimsIn breast cancer models, the functional roles of CD147 in proliferation, invasion and treatment resistance have been widely reported. However, there are only a few studies examining the clinicopathological correlation and prognostic relevance of CD147 in breast cancer, especially in relation to breast cancer molecular subtypes.MethodsIn this study, we analysed CD147 expression in a large cohort of breast cancers, correlating with clinicopathological features and the expression of a comprehensive panel of biomarkers in triple-negative breast cancer (TNBC) and non-TNBC subsets. Its relationship with patients’ survival was also analysed.ResultsCD147 was expressed in 11.9%(140/1174) of all cases and in 23.8% (40/168) of TNBC. The expression was associated with tumour histological subtypes (p=0.01) and most commonly seen in carcinoma with medullary features (26.0%). CD147 expression correlated with high tumour grade, presence of necrosis and basal-like breast cancer (BLBC) subtype, high Ki67 and expression of some other basal markers and stem-like markers. CD147 expression was also associated with poor overall survival in chemotherapy treated patients with TNBC.ConclusionsCD147 is a putative marker in identifying TNBC or BLBC, and may be useful as a prognosis indicator for patients with TNBC or BLBC post chemotherapy.

scholarly journals P08.03 Combining PD-1/PD-L1 blockade and RANKL inhibitors to treat breast cancers unresponsive to standard therapy

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A50.2-A51
Author(s):  
C Pilard ◽  
P Roncarati ◽  
E Hendrick ◽  
A Lebeau ◽  
D Bruyère ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immune Checkpoint Inhibitors ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Promising Strategy

BackgroundIn the past decade, immunotherapy using immune checkpoint inhibitors (especially targeting the PD-1/PD-L1 axis) has been demonstrated as a promising strategy for the treatment of cancers that do not respond to classical chemoradiotherapy. Given that cancer cells have the potential to express many immunosuppressive molecules other than PD-L1, the combination of immune checkpoint inhibitors with other drugs thwarting tumor immunosuppressive microenvironment could represent a promising strategy. Among these immunosuppressive molecules, RANKL, a member of the TNF superfamily, which mainly affects the immune system and bone remodeling, has been shown to be a key factor promoting the progression of breast cancer. In addition, RANKL induces the formation of tolerogenic dendritic cells and Treg cells, which promotes immunotolerance to the tumor.The aim of this research project is to study the impact of several RANKL inhibitors on triple negative breast cancer and to analyze the efficiency of their association with anti-PD-1/PD-L1 agents.Materials and MethodsWe studied RANKL and PD-L1 expression in several murine and human breast cancer cell lines by immunohistochemistry. The secretion of RANKL was analyzed by ELISA. Inhibitors of RANKL were then tested in vitro. We selected several RANKL inhibitors: anti-RANKL antibody, RANK-Fc, Isoliquiritigenin and Gallocatechin gallate. The efficacy of these inhibitors was indirectly evaluated with the murine macrophage RAW264.7 cell line which undergoes, in the presence of RANKL, an osteoclast differentiation (TRAP and Cathepsin K expression). The efficacy of RANKL inhibitors was then evaluated, in this model, by RT-qPCR. Apoptosis and proliferation of the cancer cell lines in the presence of the inhibitors were also analyzed.ResultsRANKL/PD-L1 expression profile on specimens from each breast cancer subtypes showed that both immunosuppressive molecules are expressed by all breast cancers with a significantly more intense immunoreactivity for triple negative breast cancers. Most of the cell lines expressed both proteins. We found that RANKL is secreted in their extracellular environment. RANKL inhibitors are efficient and will be tested in vivo.ConclusionsSeveral murine triple negative breast cancer cell lines will be sub-cutaneously injected in mice and the efficacy of both RANKL and PD-L1 inhibitors will be evaluated (separately or in combination). The infiltration of tumor microenvironment by different immune cell populations, the presence of metastasis and the tumor growth will be analyzed.Disclosure InformationC. Pilard: None. P. Roncarati: None. E. Hendrick: None. A. Lebeau: None. D. Bruyère: None. T. Lerho: None. M. Ancion: None. C. Reynders: None. P. Delvenne: None. M. Herfs: None. P. Hubert: None.

scholarly journals Identification and Validation of a Novel Biologics Target in Triple Negative Breast Cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vikram B. Wali ◽  
Gauri A. Patwardhan ◽  
Vasiliki Pelekanou ◽  
Thomas Karn ◽  
Jian Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
De Novo ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Tnbc Cell

Abstract The goal of this study was to identify a novel target for antibody-drug conjugate (ADC) development in triple negative breast cancer (TNBC), which has limited treatment options, using gene expression datasets and in vitro siRNA/CRISPR and in vivo functional assays. We analyzed 4467 breast cancers and identified GABRP as top expressed gene in TNBC with low expression in most normal tissues. GABRP protein was localized to cell membrane with broad range of receptors/cell (815–53,714) and expressed by nearly half of breast cancers tissues. GABRP gene knockdown inhibited TNBC cell growth and colony formation in vitro and growth of MDA-MB-468 xenografts in nude mice. Commercially available anti-GABRP antibody (5–100 μg/ml) or de novo generated Fabs (20 μg/ml) inhibited TNBC cell growth in vitro. The same antibody conjugated to mertansine (DM1) also showed significant anticancer activity at nanomolar concentrations. Our results indicate that GABRP is a potential novel therapeutic target for ADC development.

Dissecting the Heterogeneity of Triple-Negative Breast Cancer

2012 ◽  
Vol 30 (15) ◽  
pp. 1879-1887 ◽  
Author(s):  
Otto Metzger-Filho ◽  
Andrew Tutt ◽  
Evandro de Azambuja ◽  
Kamal S. Saini ◽  
Giuseppe Viale ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Parp Inhibitor ◽  
High Sensitivity ◽  
Phase Iii ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

scholarly journals XRCC1 deficient triple negative breast cancers are sensitive to ATR, ATM and Wee1 inhibitor either alone or in combination with olaparib

2020 ◽  
Vol 12 ◽  
pp. 175883592097420
Author(s):  
Reem Ali ◽  
Adel Alblihy ◽  
Michael S. Toss ◽  
Mashael Algethami ◽  
Rabab Al Sunni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Triple Negative ◽  
Germ Line ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Breast Cancers ◽  
Single Strand Break

Background: PARP inhibitor (PARPi) monotherapy is a new strategy in BRCA germ-line deficient triple negative breast cancer (TNBC). However, not all patients respond, and the development of resistance limits the use of PARPi monotherapy. Therefore, the development of alternative synthetic lethality strategy, including in sporadic TNBC, is a priority. XRCC1, a key player in base excision repair, single strand break repair, nucleotide excision repair and alternative non-homologous end joining, interacts with PARP1 and coordinates DNA repair. ATR, ATM and Wee1 have essential roles in DNA repair and cell cycle regulation. Methods: Highly selective inhibitors of ATR (AZD6738), ATM (AZ31) and Wee1 (AZD1775) either alone or in combination with olaparib were tested for synthetic lethality in XRCC1 deficient TNBC or HeLa cells. Clinicopathological significance of ATR, ATM or Wee1 co-expression in XRCC1 proficient or deficient tumours was evaluated in a large cohort of 1650 human breast cancers. Results: ATR (AZD6738), ATM (AZ31) or Wee1 (AZD1775) monotherapy was selectively toxic in XRCC1 deficient cells. Selective synergistic toxicity was evident when olaparib was combined with AZD6738, AZ31 or AZD1775. The most potent synergistic interaction was evident with the AZD6738 and olaparib combination therapy. In clinical cohorts, ATR, ATM or Wee1 overexpression in XRCC1 deficient breast cancer was associated with poor outcomes. Conclusion: XRCC1 stratified DNA repair targeted combinatorial approach is feasible and warrants further clinical evaluation in breast cancer.

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