Dataset Information

Molecular Heterogeneity of Triple Negative Breast Cancer.

ABSTRACT: Triple-negative breast cancers (TNBCs) are known to be an aggressive group of breast cancers with higher rates of relapse stage for stage compared to ER/PR positive and HER2 positive breast cancers despite optimal loco-regional and systemic therapies. To date, not a single targeted therapy has been approved for the treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Recently, gene expression analyses identified six distinct TNBC subtypes, each displaying a unique biology. In this review we will discuss current and upcoming therapeutic strategies exploring novel approaches to targeted treatment of these TNBC subtypes.

SUBMITTER: Abramson VG

PROVIDER: S-EPMC4235783 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Heterogeneity of Triple Negative Breast Cancer.

Abramson Vandana G VG Mayer Ingrid A IA

Current breast cancer reports 20140901 3

Triple-negative breast cancers (TNBCs) are known to be an aggressive group of breast cancers with higher rates of relapse stage for stage compared to ER/PR positive and HER2 positive breast cancers despite optimal loco-regional and systemic therapies. To date, not a single targeted therapy has been approved for the treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Recently, gene expression analyses identified six distinct TNBC subtypes, each displaying a uniq ...[more]

PMID: 25419441

Similar Datasets

Project description:BackgroundRecent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple-negative breast cancers (TNBCs) reporting, at least six different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.Patients and methodsThis study was carried out using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas. TNBC samples (n?=?550) were classified according to Lehmann's molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).ResultsEach subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR?=?0.68; CI?=?0.46-0.99; P?=?0.043) whereas LAR subtype was associated with a worst prognosis (HR?=?1.47; CI?=?1.0-2.14; P?=?0.046). BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 and TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.ConclusionOur findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anticancer therapeutics for TNBC.

Project description:Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.

Dataset Information

Molecular Heterogeneity of Triple Negative Breast Cancer.

Publications

Molecular Heterogeneity of Triple Negative Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets