Triple negative breast cancer (TNBC) is associated with a poor prognosis compared to other types of breast cancer. The classification of ‘triple negative’ is not one homogenous tumor type, but rather is made up of multiple molecularly and biologically diverse tumor subtypes. At present, no approved targeted therapy exists and the standard remains cytotoxic chemotherapy. The identification of TNBC subtypes has provided a basis for identifying possible targeted therapeutic options. In addition, the recognition that some TNBCs share characteristics similar to tumors arising in patients with germline BRCA mutations has led to consideration of DNA damaging agents as a potential treatment option. Multiple investigational approaches are also underway, including immune checkpoint inhibition, poly (ADP-ribose) polymerase inhibition, and androgen receptor blockage. The limited options available for systemic treatment of TNBC will hopefully expand as more is learned about the complex biology and molecular targets of this group of breast cancers. This review will discuss the biology of TNBC, current treatment options, and promising experimental strategies.
Triple negative, breast cancer, therapeutics
Tarah Ballinger, Jill Kremer and Kathy Miller have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
September 09, 2016 Accepted
October 15, 2016
Kathy Miller, Indiana Cancer Pavilion, Suite 473, 535 Barnhill Dr, Indianapolis, IN 46202-5289, US. E: email@example.com
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Triple negative breast cancer (TNBC) is defined by a lack of expression of estrogen receptor (ER) and progesterone receptor (PR), and a lack of overexpression or amplification of human epidermal growth factor 2 (HER2) on tumor cells. TNBC accounts for approximately 15–20% of all breast cancers diagnosed in the United States.1 It is more common in African American women, younger women, and those with a germline BRCA1 mutation. Due to lack of ER, PR, and HER2 and the significant heterogeneity among TNBC, no approved targeted therapies exist and standard treatment remains cytotoxic chemotherapy. While response rates to chemotherapy in early stage disease are high, patients remain at high risk for relapse and prognosis remains inferior to other types of breast cancer.
Subtyping and molecular characteristics
In a seminal paper by Perou et al., gene expression profiling was used to categorize breast cancers into five molecular subtypes. The basal-like type is characterized by lack of ER, PR, and HER2 expression, expression of cytokeratins and EGFR, and a clinically more aggressive phenotype.2 This subtype overlaps with TNBC but the terms are not synonymous; in fact, about one fourth of TNBCs are not basal-like by gene expression, and some non-TNBCs are basal-like by molecular profiling (see Figure 1).3,4 As more is discovered about the biology of TNBC, it has become clear that this category of breast cancer is not one homogeneous tumor type, but rather is made up of a group of molecularly diverse tumor subtypes. These subtypes have varying gene expression profiles, clinical characteristics, and responses to treatment. In an effort to translate the heterogeneity of TNBC into rational clinical design, Lehmann and colleagues further characterized TNBC into six distinct subtypes based on molecular profiles, each with unique drivers and clinical phenotypes. These subtypes include basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor(LAR).5 Each exhibited different sensitivities to therapeutic agents, both in cell line models and in some retrospective clinical trials. For example, the BL1 subtype responds preferentially to platinum agents and responds significantly better to neoadjuvant chemotherapy than the BL2 subtype. The mesenchymal and luminal subtypes have greater sensitivity to phosphatidylinositol 3- kinase (PI3K) pathway inhibitors, while the LAR subtype is more sensitive to androgen receptor antagonists, with a relative insensitivity to standard chemotherapy.5–9
This heterogeneity and the lack of targetable oncogenic mutations have made the development of novel strategies for TNBC difficult. Common genomic alterations in TNBC result in dysregulated cell cycle progression and resistance to apoptosis, including the loss of TP53, RB1, BRCA1, and PTEN, as well as gain of function alterations in the cyclins/cyclin-dependent kinases (CCNE1, CCND1, CDK4, CDK6) and the PI3K pathway, including PIK3CA mutations.10–12 The most common of these alterations
is a mutation or loss of TP53, which is present in 68% of TNBCs and 80% of basal-like breast cancers in The Cancer Genome Atlas (TCGA), but is yet to have a targeted therapeutic agent.10
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Triple negative, breast cancer, therapeutics