Current and emerging treatment options in triple-negative breast cancer

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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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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Triple-Negative Breast Cancer: Adjuvant Therapeutic Options

Chemotherapy Research and Practice ◽

10.1155/2011/696208 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 17

Author(s):

Ayca Gucalp ◽

Tiffany A. Traina

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Progesterone Receptors ◽

Cytotoxic Chemotherapy ◽

Breast Cancers ◽

Targeted Agents ◽

Increased Risk ◽

Disproportionate Number

Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.

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Drug-Induced Resistance and Phenotypic Switch in Triple-Negative Breast Cancer Can Be Controlled via Resolution and Targeting of Individualized Signaling Signatures

Cancers ◽

10.3390/cancers13195009 ◽

2021 ◽

Vol 13 (19) ◽

pp. 5009

Author(s):

Swetha Vasudevan ◽

Ibukun A. Adejumobi ◽

Heba Alkhatib ◽

Sangita Roy Chowdhury ◽

Shira Stefansky ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Patient Specific ◽

Network Structures ◽

Breast Cancers ◽

Drug Induced ◽

Tcga Dataset

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1–4 altered protein–protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development.

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Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Medicina ◽

10.3390/medicina57080837 ◽

2021 ◽

Vol 57 (8) ◽

pp. 837

Author(s):

So-Woon Kim ◽

Jinah Chu ◽

Sung-Im Do ◽

Kiyong Na

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Histological Grade ◽

Growth Factor Receptor ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B ◽

Epidermal Growth

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

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Identifying Biomarkers to Pair with Targeting Treatments within Triple Negative Breast Cancer for Improved Patient Stratification

Cancers ◽

10.3390/cancers11121864 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1864 ◽

Cited By ~ 2

Author(s):

Holly Tovey ◽

Maggie Chon U. Cheang

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

High Throughput Sequencing ◽

Triple Negative ◽

Treatment Options ◽

Unmet Need ◽

Growth Factor Receptor ◽

Parp Inhibitors ◽

Genetic Features ◽

The Uk

The concept of precision medicine has been around for many years and recent advances in high-throughput sequencing techniques are enabling this to become reality. Within the field of breast cancer, a number of signatures have been developed to molecularly sub-classify tumours. Notable examples recently approved by National Institute for Health and Care Excellence in the UK to guide treatment decisions for oestrogen receptors (ER)+ human epidermal growth factor receptor 2 (HER2)- patients include Prosigna® test, EndoPredict®, and Oncotype DX®. However, a population of still unmet need are those with triple negative breast cancer (TNBC). Accounting for 15–20% of patients, this population has comparatively poor prognosis and as yet no targeted treatment options. Studies have shown that some patients with TNBC respond favourably to DNA damaging drugs (carboplatin) or agents which inhibit DNA damage response (poly ADP ribose polymerase (PARP) inhibitors). Known to be a heterogeneous population, there is a need to identify further TNBC patients who may benefit from these treatments. A number of signatures have been identified based on association with treatment response or specific genetic features/pathways however many of these were not restricted to TNBC patients and as of yet are not common practice in the clinic.

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Practical Approach to Triple-Negative Breast Cancer

Journal of Oncology Practice ◽

10.1200/jop.2017.022632 ◽

2017 ◽

Vol 13 (5) ◽

pp. 293-300 ◽

Cited By ~ 24

Author(s):

Vijayakrishna K. Gadi ◽

Nancy E. Davidson

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Hormone Receptors ◽

Triple Negative ◽

Early Stage ◽

Management Strategies ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Epidermal Growth ◽

Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

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Immunotherapeutic Approaches in Triple-Negative Breast Cancer: State of the Art and Future Perspectives

International Journal of Breast Cancer ◽

10.1155/2020/8209173 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Karima Oualla ◽

Loay Kassem ◽

Lamiae Nouiakh ◽

Lamiae Amaadour ◽

Zineb Benbrahim ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Tumor Infiltrating Lymphocytes ◽

Standard Of Care ◽

Breast Cancers ◽

Poor Outcomes ◽

Infiltrating Lymphocytes

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It accounts for 15%–20% of all breast cancers and is associated with an aggressive evolution and poor outcomes with the majority of recurrences and deaths occurring in the first 5 years. Chemotherapy remains the mainstay of treatment in the absence of effective targets, but the good understanding of immune tumor microenvironment, the identification of immune-related targets, and the role of tumor-infiltrating lymphocytes (TILs) in TNBC has allowed to develop promising immunotherapeutic strategies for this unique subset of breast cancer. Recently, immunotherapy is being extensively explored in TNBC and clinical trials have shown promising results. In this article, we tried to explain the rationale and mechanisms of targeting the immune system in TNBC, to report the results from recent clinical trials that put immunotherapy as a new standard of care in TNBC in addition to ongoing trials and future directions in the next decade.

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Claudin 1, 3, 4, and 7 expression in triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.1070 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 1070-1070

Author(s):

Beom Seok Ko ◽

Hee Jeong Kim ◽

Jong Han Yu ◽

jong Won Lee ◽

Byung Ho Sohn ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Disease Free Survival ◽

Endocrine Treatment ◽

Lymph Node Status ◽

High Recurrence Rate ◽

Breast Cancers

1070 Background: Triple negative breast cancer (TNBC) often grows rapidly and has poor prognosis, with a high recurrence rate. Because conventional endocrine treatment and HER2 targeted therapy for TNBC is invalid, chemotherapy is the only systemic treatment for TNBC. It is known that several subtypes within the TNBC show different responses to chemotherapy, depending on the subtypes. Recently, a claudin (CLDN) low breast cancer has been identified, exhibiting low expressions of CLDNs 1, 3, 4 and 7. CLDNs are transmembrane proteins that seal tight junctions and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Methods: Surgically removed, formalin-fixed, paraffin-embedded breast cancers from 341 TNBC patients were analyzed to identify CLDN expression.They underwent wide local excision or mastectomy between March, 2004 and December, 2007 at the breast surgery unit of Asan Medical Central Hospital. Results: In our tumor series, we found 45.0% (153/339) of high expressing cases for CLDN1, 57.0% (192/337) for CLDN3, 57.6% (194/337) for CLDN4 and 44.0% (149/339) for CLDN7. Overall, we found 20.5% (70/341) of cases were within the low CLDN expression group and 79.5% (271/341) of tumors were within the high expression group of CLDN1, 3, 4 ,7. Although the high CLDN expression group was significantly associated with positive lymph node status and higher stage, there were no significant differences between CLDN low and high groups in disease free survival (p=0.477) or overall survival (p=0.253). Conclusions: CLDN high tumors are associated with poor prognosis features, but they are not an independent prognostic factor in TNBC patients. However, the mechanisms underlying the different roles of CLDNs in tumorigenesis are largely unclear. Studying the associations of these CLDNs with the TNBC subgroup of breast cancers might provide us with potential diagnostic biomarkers or therapeutic targets for cancer cells.

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Development of Targeted Therapy Therapeutics to Sensitize Triple-Negative Breast Cancer Chemosensitivity Utilizing Bacteriophage phi29 Derived Packaging RNA

10.21203/rs.3.rs-51875/v1 ◽

2020 ◽

Author(s):

Long Zhang ◽

Chaofeng Mu ◽

Tinghong Zhang ◽

Dejun Yang ◽

Luhui Fan ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Sirna Delivery ◽

Growth Factor Receptor ◽

Her2 Breast Cancer ◽

Packaging Rna

Abstract Background: To date, triple-negative breast cancer (TNBC) treatment options are limited due to it lacks expression of receptors and are only available managed with chemotherapy. What's worse, TNBC is frequently developing resistance to chemotherapy. By using siRNA-based therapeutics, our recent work demonstrated X-box-binding protein 1 (XBP1) was linked to HER2+ breast cancer development and chemoresistance. As is well-known, the instability, off-target effects, net negative charge, and hydrophobicity of siRNA hamper its’ in vivo utilization and clinical transformation. Thus, the development of a siRNA delivery system (DDS) with ultra-stability and specificity is demanded to address the predicament of siRNA delivery.Results: Here, we assembled RNase resistant RNA nanoparticles (NPs) based on the 3WJ of Phi29 DNA packaging motor. To targeted therapy and sensitize TNBC to chemotherapy, the RNA NPs were equipped with epidermal growth factor receptor (EGFR) targeting aptamer and XBP1 siRNA. We found our RNA NPs could deplete XBP1 expression and suppress tumor growth after intravenous administration. Meanwhile, RNA NPs treatment could promote the sensitization of chemotherapy and impair angiogenesis in vivo. Conclusions: The results further demonstrate that our RNA NPs could serve as an effective and promising platform not only for siRNA delivery but also for chemotherapy-resistant TNBC therapy.

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Clinical-Epidemiological profile of patients with triple-negative breast cancer at instituto Mario Penna, Belo Horizonte, Minas Gerais

Mastology ◽

10.29289/259453942020v30s1054 ◽

2020 ◽

Vol 30 (Suppl 1) ◽

Author(s):

Ana Luiza de Freitas Magalhães Gomes ◽

Marina Paixão de Madrid Whyte ◽

Wagner Antonio Paz ◽

Kerstin Kapp Rangel ◽

Paulo Guilherme de Oliveira Salles

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

Limiting Factor ◽

Breast Cancers ◽

Missing Information ◽

Belo Horizonte ◽

Epidemiological Profile

Introduction: Triple-negative breast cancer (TNBC) does not express estrogen and progesterone receptors, and does not overexpress the human epidermal growth factor 2. It represents 15%‒20% of breast cancers and have worse prognosis, with scarce available therapies and overall survival (OS) of 18 months. For these particularities, research on TNBC is important for its greater understanding. Objectives: To describe the clinical-epidemiological profile of patients with TNBC at Instituto Mário Penna (IMP). To compare findings with data from the literature. Methods: Consultation of breast immunohistochemistry (IHC) performed at IMP between July/2012 and June/2017. TNBC were selected. Data were collected from patients in electronic medical records. Maximum follow-up until December/2018. Database and statistical analysis using the SPSS program. Bibliographic review used the key phrase: “triple-negative breast cancer”. Results: 1,343 breast IHC performed at IMP in the studied period, 168 were TNBC (12.5%). Mean age of 53.4 years. Mean follow-up of 41.7 months. Neoadjuvant chemotherapy (CT) performed in 46.4%, with 12.8% of complete pathological response. Mean SG of 23.6 months, 20.2% progressed before the end of the treatment. Tumor mean size of 4.04 cm. Mortality of 22%, with 31.5% without information on death in the medical record, and about 17% on average with missing information. Table 1 shows the frequency distribution of the variables evaluated. Discussion: TNBC is a heterogeneous group of diseases, more commonly found in people aged under 40 years, of African descent, diagnosed at an advanced stage and with a high histological grade. Earlier metastasis, preferably visceral. More sensitive to CT, but with worse OS compared to other subtypes. Use of platinum, capecitabine and recent studies with immunotherapy are promising, in the search for better outcomes. Conclusion: The profile of patients with TNBC in IMP is compatible with that described in the literature. This study is a hypothesis generator and the basis for more complex research. High rates of missing information are a limiting factor.

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