Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles, which are aggregated under ...this term because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Massively parallel sequencing and other omics technologies have demonstrated the level of heterogeneity in TNBCs and shed light into the pathogenesis of this therapeutically challenging entity in breast cancer. In this review, we discuss the histologic and molecular classifications of TNBC, the genomic alterations these different tumor types harbor, and the potential impact of these alterations on the pathogenesis of these tumors. We also explore the role of the tumor microenvironment in the biology of TNBCs and its potential impact on therapeutic response. Dissecting the biology and understanding the therapeutic dependencies of each TNBC subtype will be essential to delivering on the promise of precision medicine for patients with triple-negative disease.
As cancer cell genomes are unveiled at a breathtaking pace, the genetic principles at play in cancer are emerging in all their complexity, prompting the assessment of classical genetic interaction ...models. Here, we discuss the implications of these findings for cancer progression and heterogeneity and for the development of new therapeutic approaches.
Microarray-based gene expression profiling has had a major effect on our understanding of breast cancer. Breast cancer is now perceived as a heterogeneous group of different diseases characterised by ...distinct molecular aberrations, rather than one disease with varying histological features and clinical behaviour. Gene expression profiling studies have shown that oestrogen-receptor (ER)-positive and ER-negative breast cancers are distinct diseases at the transcriptomic level, that additional molecular subtypes might exist within these groups, and that the prognosis of patients with ER-positive disease is largely determined by the expression of proliferation-related genes. On the basis of these principles, a molecular classification system and prognostic multigene classifiers based on microarrays or derivative technologies have been developed and are being tested in randomised clinical trials and incorporated into clinical practice. In this review, we focus on the conceptual effect and potential clinical use of the molecular classification of breast cancer, and discuss prognostic and predictive multigene predictors. PUBLICATION ABSTRACT
Summary Microarray-based gene expression profiling has had a major effect on our understanding of breast cancer. Breast cancer is now perceived as a heterogeneous group of different diseases ...characterised by distinct molecular aberrations, rather than one disease with varying histological features and clinical behaviour. Gene expression profiling studies have shown that oestrogen-receptor (ER)-positive and ER-negative breast cancers are distinct diseases at the transcriptomic level, that additional molecular subtypes might exist within these groups, and that the prognosis of patients with ER-positive disease is largely determined by the expression of proliferation-related genes. On the basis of these principles, a molecular classification system and prognostic multigene classifiers based on microarrays or derivative technologies have been developed and are being tested in randomised clinical trials and incorporated into clinical practice. In this review, we focus on the conceptual effect and potential clinical use of the molecular classification of breast cancer, and discuss prognostic and predictive multigene predictors.
Summary Despite the success of targeted therapies in the treatment of cancer, the development of resistance limits the ability to translate this method into a curative treatment. The mechanisms of ...resistance have traditionally been thought of as intrinsic (ie, present at baseline) or acquired (ie, developed after initial response). Recent evidence has challenged the notion of acquired resistance. Although cancers are traditionally thought to be clonal, there is now evidence of intra-tumour genetic heterogeneity in most cancers. The clinical pattern of acquired resistance in many circumstances represents outgrowth of resistant clones that might have originally been present in the primary cancer at low frequency but that have expanded under the selective pressure imposed by targeted therapies. Here, we describe the potential role of clonal heterogeneity in resistance to targeted therapy, discuss genetic instability as one of its causes, and detail approaches to tackle intra-tumour heterogeneity in the clinic.
Triple-negative breast cancer Foulkes, William D; Smith, Ian E; Reis-Filho, Jorge S
The New England journal of medicine,
11/2010, Letnik:
363, Številka:
20
Journal Article
Recenzirano
Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review ...focuses on its origin, molecular and clinical characteristics, and treatment.
Breast cancer is a complex and heterogeneous disease, comprising multiple tumor entities associated with distinctive histological patterns and different biological features and clinical behaviors. ...Microarray-based high-throughput technologies have been employed to unravel the molecular characteristics of breast cancer, including its proclivity to disseminate to distant sites, and the molecular basis for histological grade. In addition, a breast cancer molecular taxonomy based solely on transcriptomic analysis has been proposed. Most microarray studies have focused on invasive ductal carcinomas of no special type, neglecting the important information about the biology and clinical behavior of breast cancers conveyed by histological type. Histological special types of breast cancer account for up to 25% of all invasive breast cancers. The histopathological characteristics of these cancers might be driven by specific genetic alterations, providing direct evidence for genotypic-phenotypic correlations between morphological patterns and molecular changes in breast cancer. We review the historical aspects of breast cancer taxonomy, discuss the possible origins of the diversity of breast cancer and propose an approach for the identification of novel therapeutic targets on the basis of histological special types of breast cancer.
We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS. We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF ...activation, and MEK–ERK signaling. This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibition per se does not drive pathway activation; it only occurs when BRAF is inhibited in the presence of oncogenic RAS. Kinase-dead BRAF mimics the effects of the BRAF-selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Our data reveal another paradigm of BRAF-mediated signaling that promotes tumor progression. They highlight the importance of understanding pathway signaling in clinical practice and of genotyping tumors prior to administering BRAF-selective drugs, to identify patients who are likely to respond and also to identify patients who may experience adverse effects.
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► BRAF activates ERK but in some circumstances BRAF inhibitors can induce tumor growth ► BRAF inhibitors drive BRAF-CRAF binding, activating ERK in cells with oncogenic RAS ► Kinase-dead mutants of BRAF have the same effect as BRAF inhibitors ► Oncogenic RAS and kinase-dead BRAF cooperate to induce melanoma in mice
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