Triple negative breast cancers: Clinical and prognostic implications

Abstract

Triple negative breast cancers are defined by the absence of oestrogen, progesterone and HER2 expression. Most triple negative cancers display distinct clinical and pathological characteristics with a high proportion of these tumours occurring at a younger age of onset and in African–American women. Triple negative tumours typically demonstrate high histological grade and are the most common breast cancer subtype in BRCA1 carriers. In addition, many of the features of triple negative cancers are similar to those identified in the basal-like molecular subtype which has recently been characterised by gene expression profiling. Although the two groups overlap, they are not synonymous. Triple negative breast cancers are of pivotal clinical importance given the lack of therapeutic options. The prognostic significance of triple negative tumours remains unclear since the group is heterogeneous and worst prognosis seems to be mostly confined to those that express basal cytokeratins or epidermal growth factor receptor (EGFR). This review focuses on outlining the pathological, molecular, and clinical features of triple negative breast cancers, discusses its prognostic value and summarises current therapeutic approaches and future directions of research.

Introduction

The classification of invasive breast cancer for prognostic and predictive evaluation currently involves the assessment of histological criteria encompassing both morphology-based and immunohistochemical analysis. Traditional pathological parameters such as tumour size, axillary lymph node involvement and histological grade have been shown to correlate with prognosis [1, 2]. Immunohistochemical markers such as the expression of hormone receptors (oestrogen (ER) and progesterone receptors (PR)) and the overexpression (or amplification) of HER2 provide therapeutic predictive value and are of key importance in guiding treatment selection [3]. Hormone receptor positive breast cancers account for around 75–80% of all cases. In contrast, HER2 positive tumours are identified in approximately 15–20%, with around half of these coexpressing hormone receptors [4]. The remaining 10–15% of breast cancers are defined by hormone receptor and HER2 negativity (i.e. triple negative cancers) [5, 6, 7]. Whilst effective targeted therapeutic modalities exist for women with hormone receptor positive and HER2 positive disease, chemotherapy is the only systemic therapy available for women with triple negative disease. The relatively aggressive clinical course, poor prognosis and lack of therapeutic options for this type of tumour have intensified current interest in this patient group.

Whilst the classification of human breast tumours on the basis of histological criteria has proven useful, there are a number of important limitations. Firstly, considerable variation in response to therapy and clinical outcome exists, even for tumours with apparent similarities in clinical and pathological characteristics. Secondly, this classification provides limited insight into the biology of breast cancer and the molecular pathways driving the disease. In recent years, gene expression profiling using microarray-based technology has provided a new way to classify human breast tumours and has resulted in the identification of clinically relevant molecular subtypes of breast cancer: luminal A, luminal B, HER2 overexpressing, normal breast tissue-like and basal-like cancers [8, 9, 10, 11]. The difference in the gene expression patterns among the subtypes reflects basic alterations in the cell biology of the tumours. In addition, the molecular differences between the tumour subtypes have been associated with significant variation in clinical outcome [11, 12]. Basal-like breast cancers have been identified using gene expression profiling; however, no validated consensus for the routine clinical identification of this subtype or other intrinsic subtypes of breast cancer exists. The features of basal-like breast cancers, as defined by microarrays, include the low expression of hormone receptor and HER2 amplicon genes. Therefore, in clinical specimens, basal-like breast cancers are often ER negative, PR negative and HER2 negative (i.e. triple negative cancers). The observed overlap between the triple negative phenotype and the basal-like breast cancer profile has provided new insights into this important subgroup of cancers, but has also created confusion.