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Triple-negative breast cancer 

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  1. 21-07-2021 | Breast cancer | News | Article

    KEYNOTE-522 supports pembrolizumab for early triple-negative breast cancer

    Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab significantly improves event-free survival rates versus neoadjuvant chemotherapy alone in people with a new diagnosis of early-stage triple-negative breast cancer, KEYNOTE-522 study data show.

  2. 10-06-2021 | ASCO 2021 | Conference coverage | Article

    Long-term benefits to neoadjuvant durvalumab in triple-negative breast cancer

    Adding the PD-L1 inhibitor durvalumab to neoadjuvant chemotherapy may improve survival outcomes in people with triple-negative breast cancer, show GeparNUEVO data presented at the 2021 ASCO Annual Meeting.

  3. 27-10-2018 | Triple-negative breast cancer | Teaser
    medwireNews editor's pick

    IMpassion130 supports atezolizumab use in triple-negative breast cancer

    Results for the IMpassion130 trial support the combination of atezolizumab and nab-paclitaxel for the treatment of metastatic triple-negative breast cancer, especially among patients with programmed cell death ligand 1-positive disease.

  4. 21-10-2018 | Triple-negative breast cancer | News | Article

    IMpassion130 supports atezolizumab use in triple-negative breast cancer

    Results for the IMpassion130 trial support the combination of atezolizumab and nab-paclitaxel for the treatment of metastatic triple-negative breast cancer, especially among patients with programmed cell death ligand 1-positive disease.

  5. 14-08-2017 | Teaser

    Triple-negative breast cancer

    This book chapter explores newly-discovered molecular subtypes of triple-negative breast cancer and how genetic profiling can be used to target therapy. Summary points Triple-negative breast cancers (TNBC) are those that lack expression of the breast cancer prognostic markers estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), and account for about 15% of all breast cancers. Recent increased understanding of the molecular mechanisms responsible for the initiation and propagation of this breast cancer subtype has been gained through gene expression profiling, the study of cancer genetics and the study of host antitumor immunity. The majority of TNBCs cluster within a basal-like subgroup, characterized by a low expression of hormone receptor and HER2-related genes and high expression of proliferation genes characteristic of the basal epithelial cell layer. The therapeutic significance of basal-like versus non-basal-like TNBC is yet to be determined. Despite this association, substantial molecular heterogeneity in TNBC defined by immunophenotyping exists. Six subtypes of TNBC have been identified, including two basal-like (BL-1 and BL-2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Breast cancer in women with a germline BRCA1 mutation are overwhelmingly triple negative. Given the known role of BRCA1 and BRCA2 in homologous recombination DNA repair, treatment with platinum chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors has been associated with high levels of anticancer activity. In addition to germline BRCA1 and BRCA2 mutation status, biomarkers of genomic instability have been developed that detect genomic ‘scarring’ caused by accumulated DNA damage. Therapeutic strategies are currently being investigated to assess whether these germline and genetic biomarkers can identify groups of patients with TNBC with underlying DNA repair deficiency more likely to benefit from DNA repair defect targeted therapies. Telli ML. In: Molecular Pathology of Breast Cancer . Edited by Badve S and Gökmen-Polar Y. Springer, Cham, 2016. doi:10.1007/978-3-319-41761-5_6

  6. 14-08-2017 | Teaser

    Metabolic characterization of triple negative breast cancer

    This study aimed to characterize the metabolite profiles of triple-negative breast cancer in comparison with ‘triple-positive’ breast cancer, and how this may help targeted treatment strategies. Summary points This study aimed to characterize the metabolite profiles of triple-negative breast cancer (TNBC) in comparison with triple-positive breast cancer (TPBC; estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2] positive). The influences of ER, PR and HER2 status individually on breast cancer metabolism were also examined. 75 patients aged 34 to 90 and diagnosed with breast cancer without known distant metastases were included in this study. Tumor metabolite content was identified and quantified using high resolution magic angle spinning magnetic resonance spectroscopy. Choline levels were found to be higher in TNBC compared to TPBC, which is possibly related to cell proliferation and oncogenic signaling. TNBC tumors also had a lower level of glutamine and a higher level of glutamate compared to TPBC tumors, which indicates an increase in glutaminolysis metabolism and suggests the development of glutamine dependent cell growth, or ‘glutamine addiction’. Significantly higher levels of glycine were found in HER2-positive breast cancer, which supports the potential of glycine as a marker for tumor aggressiveness. Metabolic alterations caused by the individual and combined receptors involved in breast cancer progression can provide a better understanding of the biochemical changes underlying the different breast cancer subtypes. Further research is needed to validate the potential of metabolic markers as targets for personalized treatment of breast cancer subtypes. Cao MD, Lamichhane S, Lundgren S et al. BMC Cancer 2014;14:941. doi:10.1186/1471-2407-14-941

  7. 14-08-2017 | Teaser

    Molecular heterogeneity of triple-negative breast cancer

    This review article describes the different subtypes of triple-negative breast cancer and potential therapeutic strategies and novel approaches to targeted therapy. Summary points Approximately 15% of invasive breast cancers lack expression of endocrine receptors for estrogen and progesterone (ER and PR, respectively) and human epidermal growth factor receptor 2 (HER2); these are known as ‘triple-negative breast cancers’ (TNBCs). Most TNBCs are classified as the ‘basal-like subtype’, which is characterized by lack of ER/PR/HER2 expression and increased expression of cytokeratins 5 or 6, 14, and 17, P-cadherin, p53, and epidermal growth factor receptor; however, a significant number of basal-like breast cancers do express ER/PR or HER2, and 20–30% of clinical TNBCs are not basal-like by microarray analysis. Clinically, TNBCs are a group of aggressive breast cancers with a greater incidence of relapse, stage-for-stage, than ER/PR-positive and HER2-positive breast cancers, despite optimum loco-regional and systemic therapy. Recently, gene expression analysis identified six distinct TNBC subtypes, each with unique biology and pathologic complete response. To date, no single targeted therapy has been approved for treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Potential targeted therapeutic approaches for basal-like TNBCs include poly(ADP-ribose) polymerase (PARP) inhibition, PI3K inhibition, and luminal androgen receptor targeting. Combining two or more targeted agents with or without chemotherapy may be required to develop a more rational and optimum approach to TNBC treatment, because combination of ‘complementary’ pathway inhibitors would potentially maximize efficacy, and would minimize therapeutic resistance. Abramson VG and Mayer IA. Curr Breast Cancer Rep 2014;6:154. doi:10.1007/s12609-014-0152-1

  8. 23-08-2017 | Triple-negative breast cancer | News | Article

    Ipatasertib improves PFS in triple-negative breast cancer

    Adding the oral AKT inhibitor ipatasertib to paclitaxel significantly prolongs progression-free survival, compared with placebo plus paclitaxel, when used as first-line therapy for triple-negative breast cancer, phase II study data show.

  9. 06-11-2017 | Triple-negative breast cancer | Article

    Role of Platinum in Early-Stage Triple-Negative Breast Cancer

    La Belle A et al. Curr Treat Options in Oncol 2017; 18: 68. doi:10.1007/s11864-017-0506-9

  10. 27-11-2016 | Triple-negative breast cancer | Book chapter | Article

    Triple-negative breast cancer

    This book chapter explores newly-discovered molecular subtypes of triple-negative breast cancer and how genetic profiling can be used to target therapy. Telli ML. In: Molecular Pathology of Breast Cancer . Edited by Badve S and Gökmen-Polar Y. Springer, Cham, 2016. doi:10.1007/978-3-319-41761-5_6

  11. 27-06-2018 | Triple-negative breast cancer | Article

    BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study

    Fasching PA et al. J Clin Oncol 2018; JCO2017772285. doi:10.1200/JCO.2017.77.2285

  12. 08-01-2018 | Triple-negative breast cancer | Article

    Clinical and pathological factors influencing survival in a large cohort of triple-negative breast cancer patients

    Urru SAM et al. BMC Cancer 2018; 18: 56. doi:10.1186/s12885-017-3969-y

  13. 14-08-2017 | Teaser

    Concepts and targets in triple-negative breast cancer: Recent results and clinical implications

    The discovery of subsets of triple-negative breast cancer has driven research focusing on targeted therapies. This review article provides an overview of recent developments. Summary points Due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), there are currently no targeted therapies available for triple-negative breast cancer, but the discovery of six distinct subsets of TNBC has driven research in this area. Further analysis by triple-negative subtype suggests that not only do these subtypes differ in outcome, but they also likely differ in driver mutations. Better characterization of these recurrent alterations may lead to the development of novel targeted therapies. Platinum agents, including carboplatin and cisplatin, have been investigated for TNBC in the neoadjuvant setting and have shown higher pathologic complete response (pCR) rates both in those with a BRCA1 mutation as well as those with sporadic TNBC. Promising results have been achieved with poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 -associated TNBC. In ER-negative breast cancers, high tumor glucocorticoid receptor (GR) mRNA expression correlates with a decrease in time to relapse for both chemotherapy naïve and chemotherapy treated early stage patients, suggesting a role for GR in tumor aggressiveness and resistance to chemotherapy. GR antagonism using mifepristone appears a promising approach in advanced TNBC. The luminal androgen receptor (LAR) subtype of TNBC is characterized by luminal gene expression profiling, and is enriched for expression of AR and its gene targets. Findings suggest that patients with AR-positive TNBC do not receive the same benefit from standard chemotherapy than those with AR-negative TNBC, and alternative strategies, perhaps incorporating antiandrogen agents are needed. Blockade of the programmed death receptor 1/programmed death ligand 1 axis has demonstrated promising efficacy and durable responses in advanced TNBC. The rationale for investigating immune checkpoint inhibitors in TNBC stems from a number of key observations made over the past decade, including the observation that ER-negative breast cancers have a higher density of tumor infiltrating lymphocytes. Saha P and Nanda R. Ther Adv Med Oncol  2016;8:351–359. doi:10.1177/1758834016657071

  14. 14-08-2017 | Teaser

    Androgen receptor biology in triple negative breast cancer: A case for classification as AR+ or quadruple negative disease

    This review of the literature explores the role of the androgen receptor in triple-negative breast cancer, and how it may be used as a prognostic and therapeutic target. Summary points There are currently no targeted therapies approved for triple-negative breast cancer (TNBC) due to the fact that TNBC tumors lack estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2); as such TNBC has a poor prognosis. However, some TNBC tumors express androgen receptor (AR) (nuclear AR expression [as detected by IHC] ranges from 12–55% depending on the study) and therefore may benefit from AR-targeted therapies. Emerging data suggest that AR significantly influences breast cancer gene expression profiles and affects tumorigenic properties of TNBC. Studies comparing AR expression in primary versus metastatic disease found that AR is frequently retained in metastatic samples from patients with AR+ primary tumors. The prognostic significance of AR in TNBC is controversial as AR expression has been associated with both a good and bad prognosis in multiple studies. The existence of the luminal AR (LAR) TNBC subtype, with strong AR expression driving a luminal-like expression pattern in the absence of ER, is evidence that AR signaling can play a strong role in the biology of TNBC tumors. AR expression is associated with decreased proliferation in TNBC, but LAR tumors have a particularly poor prognosis, possibly because of their poor response to chemotherapy. Anti-androgens have shown particular efficacy in preclinical studies of LAR models and may be useful in improving the treatment of LAR tumors. Recently reported and ongoing clinical trials using bicalutamide or enzalutamide (a new generation anti-androgen) in TNBC have shown an increase in progression-free survival, suggesting that AR-targeted therapies may improve patient prognosis and supporting a reclassification of TNBC into AR-positive and ‘quadruple negative’ disease. Barton VN, D’Amato NC, Gordon MA et al. Horm Canc 2015;6:206–213. doi:10.1007/s12672-015-0232-3

  15. 06-10-2017 | Breast cancer | Article

    Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer

    ​​​​​​​Mod Pathol 2017. doi:10.1038/modpathol.2017.126

  16. 14-08-2017 | Teaser

    Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response

    This study analyzed biopsies and blood samples of patients with triple-negative breast cancer in an attempt to find chemotherapy response-predictive biomarkers and to identify new treatment targets. Summary points In triple-negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. In the current study, the DNA of TNBC tumors was deep sequenced prior to chemotherapy to search for predictors of response or resistance. Next generation sequencing (NGS) was performed for 1,977 genes involved in tumorigenesis. DNA from 56 pre-treatment TNBC-biopsies was sequenced, as well as matched normal DNA. Following their tumor biopsy, patients started neoadjuvant chemotherapy with doxorubicin and cyclophosphamide; all patients subsequently underwent surgery, either breast conserving or mastectomy. The associations between genetic alterations and three clinical variables were studied: chemotherapy response, relapse-free survival and BRCA proficiency. TNBC was found to be very heterogeneous, and it was therefore not possible to identify biomarkers associated with chemotherapy response and relapse. 22% of the tumors had a BRCA mutation and 30% had BRCA1 promoter methylation, indicating that BRCA inactivation is observed in over half of the tumors. Tumors without BRCA impairment (through a mutation or through BRCA1-promoter methylation) frequently had PIK3CA mutations. After validation in larger series, TNBC tumors with PIK3CA mutations may be candidates for agents targeting these oncogenic pathways. To identify recurrent mutations associated with chemotherapy or relapse, larger sample series are urgently needed. Lips EH, Michaut M, Hoogstraat M et al. Breast Cancer Res 2015;17:134. doi:10.1186/s13058-015-0642-8

  17. 14-08-2017 | Teaser

    Gene-expression molecular subtyping of triple-negative breast cancer tumours: Importance of immune response

    This study retrospectively analyzed the microarray gene-expression profiles of 107 triple-negative breast tumors in an attempt to better understand therapeutic subgroups. Summary points This study analyzed microarray gene-expression profiles of 107 triple-negative breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. Three subtypes of triple-negative patients were identified by fuzzy clustering: C1, luminal androgen receptor (LAR) (n = 24; 22.4%); C2, basal-like with low immune response and high M2-like macrophages (n = 48; 44.9%); and C3, basal-enriched with high immune response and low M2-like macrophages (n = 35; 32.7%). Histological grade and Nottingham prognostic index (NPI) were higher in C2 and C3 than in C1, showing that C1 was different from C2 and C3, and that C1 seemed to be characterized by a less aggressive illness according to age, histological grade and NPI. Patients belonging to C3 had a better event-free survival than patients in C1 (p= 0.0145) and C2 (p = 0.0195). There was no difference in outcome between C1 and C2. Patients belonging to the C1 ‘non-basal-like’ cluster, enriched with LAR and/or human epidermal growth factor receptor 2 (HER2)-enriched characteristics, might be candidates to receive hormonotherapy or anti-HER2 therapy. Macrophages, particularly M2-like, offer a variety of therapeutic targets in TNBC patients. Jézéquel P, Loussouarn D, Guérin-Charbonnel C et al. Breast Cancer Res 2015;17:43. doi:10.1186/s13058-015-0550-y

  18. 14-08-2017 | Teaser

    Triple-negative breast cancer: The importance of molecular and histologic subtyping, and recognition of low-grade variants

    Triple-negative breast cancer (TNBC) is a vastly heterogeneous disease. This review focuses on the histologic and molecular features of low-grade forms of TNBC. Summary points Triple-negative breast cancer (TNBC) has been shown to constitute a vastly heterogeneous disease encompassing a wide spectrum of entities with marked genetic, transcriptional, histological and clinical differences. Although most TNBCs are high-grade tumors, there are well-characterized low-grade TNBCs that have an indolent clinical course, whose natural history, molecular features and optimal therapy vastly differ from those of high-grade TNBCs. Unlike other forms of breast cancer, where several genes have been found to be mutated in >10% of cases, the only known cancer genes targeted by somatic mutations in 10% or more of TNBCs are TP53 and PIK3CA. Low-grade TNBCs can be further classified into at least two subgroups: A heterogeneous group of salivary gland-like tumors of the breast, where each entity is underpinned by specific genetic fusion genes or hotspot mutations, and lack the genomic features of common forms of TNBCs. The so-called low-grade triple negative breast neoplasia family, encompassing microglandular adenosis, atypical microglandular adenosis, and acinic cell carcinoma, which are phenotypically similar and recapitulate the genetic alterations found in conventional TNBCs. A subset of TNBCs has been suggested to harbor homologous recombination DNA repair defects similar to those found in tumors arising in BRCA1 and BRCA2 mutation carriers, and as such these patients may benefit from treatment with platinum salts and poly(ADP-ribose) polymerase (PARP) inhibitors. The relevance of tumor-infiltrating lymphocytes (TILs) is increasing as a prognostic and predictive biomarker in TNBC, and guidelines from the International TIL Working Group have been published. Pareja F, Geyer FC, Marchio C et al. npj Breast Cancer  2016;2:16036. doi:10.1038/npjbcancer.2016.36

  19. 17-05-2016 | Triple-negative breast cancer | Article

    Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease

    Figure 1: The heterogenous landscape of triple-negative breast cancer.

  20. 10-07-2016 | Triple-negative breast cancer | Article

    Concepts and targets in triple-negative breast cancer: Recent results and clinical implications

    The discovery of subsets of triple-negative breast cancer has driven research focusing on targeted therapies. This review article provides an overview of recent developments. Saha P and Nanda R. Ther Adv Med Oncol  2016;8:351–359. doi:10.1177/1758834016657071

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