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Evolving Paradigms in Triple-Negative Breast Cancer: Introduction

Published Online: Feb 20,2017

Breast cancer is a leading cause of cancer deaths in women, with 12% to 20% of cases being classified as triple-negative breast cancer (TNBC). These tumors are characterized by a lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptors (HER2), which limits the use of trastuzumab and hormonal-based treatments.


Research into treatment options for TNBC is crucial because it is often diagnosed in younger women and African American women and because of its aggressive nature, poor prognosis, and lack of specific targeted therapy.1 Furthermore, compared with other subtypes, TNBC has a median survival of only 12 months and is associated with visceral metastases and recurrence within 3 years of diagnosis.2 The heterogeneous nature and limited biomarkers of TNBC have restricted the development of drugs specific to TNBC; however, new research has opened the door for targeted therapies based on distinct morphologic features.2,3



Pathophysiology of TNBC



Breast cancer is divided into 18 subtypes based on histology and morphologic characteristics. However, this does not take into account disease-specific treatment options and prognosis. Furthermore, accuracy of classification is pathologist-dependent. Additional studies into DNA microarrays allowed division based on gene expression, including expression of hormone receptors. The breast cancer subtypes luminal A, luminal B, basal-like, normal-like, and HER2-positive have individualized treatments and prognoses.4


TNBC is a heterogeneous group of tumors with an absence of HER2, ER, and PR that can be further divided into apocrine, adenoid cystic, metaplastic, and medullary histopathologic subtypes. Frequently encountered mutations in TNBC include those in TP53 and PIK3CA (FIGURE 1).3




Figure 1. Intrinsic breast cancer and TNBC subtypes relationships.


Basal-like breast cancer and TNBC


Adjacent to the basement membrane are basal cells. There is a subtype of breast cancer that expresses basal-like genes. Basal-like breast cancer occurs more often in younger patients, is more aggressive, and regularly has TP53 mutations. Basal-like breast cancers mostly fall into the TNBC classification; however, 15% to 54% are positive for PRs, ERs, and HER2.3 An estimated 75% of patients with TNBC have basal-like markers.5


When taking into account gene expression profiling related to treatment response and prognosis, basal-like breast cancers form a homogenous group, while TNBC does not. Therefore, the actual poor prognosis of TNBC may be due to the basal-like subtype that makes up a large portion of TNBC.4 Interestingly, studies have indicated a role for loss of BRCA1 function in the development of some basal-like TNBC along with DNA methylation. Likewise, studies have indicated a relationship to basal-like TNBC with epidermal growth factor receptor (EGFR) expression, which is associated with cellular growth and poor outcomes.4

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Evolving Paradigms in Triple-Negative Breast Cancer: Introduction
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