The treatment of triple negative breast cancer (TNBC) is an unmet medical need, which refers to tumors that are estrogen receptor (ER) and progesterone receptor (PR) negative, and where human epidermal growth factor receptor 2 (HER2) is not overexpressed. This subset accounts for approximately 12–20 % of breast cancer patients.1 Gene expression analysis on this heterogenous group of patients demonstrates an overlap between the molecular signature of TNBC and basal-like (BL) breast cancer (BLBC). The concordance rates between the two groups are in the order of 70–90 %. Not all TNBC can be defined as BLBC as a small minority of BLBC patients express ER and HER2 receptors. The purpose of this review is to discuss the pathologic diagnosis, current trends in management of TNBC in the neo-adjuvant, adjuvant, and metastatic disease treatment, and future directions.
Pathologic Features and Diagnosis of Triple Negative Breast Cancer
TNBC, which comprises 12–20 % of all breast cancers, are a heterogeneous group of tumors, clinically and pathologically at the molecular level.1 The defining features of this cohort of breast cancers are a lack of expression of the hormone receptors ER and PR, combined with a lack of either overexpression or amplification of the HER2 gene. The majority (around 70 %) has been demonstrated to be BLBC, and this subtype is defined by an overexpression of epidermal growth factor receptor-1 (EGFR-1) and basal cytokeratins, particularly the cytokeratin 5/6 (CK5/6), as well as cytokeratins 14 and 17. These pathologic basal cell type TNBCs have a typical histopathologic appearance, most being poorly differentiated grade 3 carcinomas, with some or all of the following microscopic features: solid growth pattern, a prominent lympho-plasmacytic infiltrate, and a medullarylike growth pattern. The tumor cells are characteristically markedly pleomorphic with pleomorphic nuclei, prominent mitotic activity, and well-marked cellular apoptosis. There is usually extensive geographic tumor necrosis, which can be associated with the exceptionally high proliferative rate of these tumors. Some exhibit prominent stromal fibrosis. Characteristically, these tumors have a ‘pushing’ rather than an infiltrative border. Most of these tumors show the BL molecular characteristics as described by Perou et al.,2 and some may show squamous differentiation and even spindle cell morphology (metaplastic carcinomas). These last two histologic variants have been regarded to be BL variants.
The PAM50 gene expression assay classifies breast cancers into at least five groups, including luminal A, luminal B, HER2 enriched, BL, and normal breast-like and this classification can be recapitulated with surrogate immunohistochemical markers, including ER, PR, HER2, EGFR1, CK5/6, and Ki67.3–5 More recent gene expression array analysis has identified six different groups of TNBC, including two BL (BL1 and BL2), an immunemodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor subtype (LAR).3 A further group termed unstable (UNS) has been recognized.6 The BL1 and 2 subtypes typically have a higher expression of cell cycle genes, while M and MSL are enriched for epithelial–M transition, and growth factor pathways. LAR, by definition, demonstrates AR overexpression.3 The study of Matsuda et al.6 has confirmed the work of Lehman.3
It is important, therefore, to note that while there is overlap between TNBC and BLBC, these two entities are not synonymous with one another and so the BL carcinoma is best regarded as a subset of TNBC. It has been demonstrated that only 71 % of TNBC are of BL subtype by gene expression profiling, and that only 77 % of molecular BLBC are triple negative.7 Up to 70 % of patients with BRCA1 mutations develop tumors that are morphologically identical to the BLBC and are often triple negative. These probably form a further subset of the basal-type carcinomas, but not all BRCA1-associated tumors are TNBC.
A recent study comparing BL TNBC assessed the three different modalities for defining TNBC, namely morphology, immunohistochemistry (IHC), and transcriptional profiles. In this study by Gazinska et al.,8 those TNBC that were positive for CK5/6 and/or EGFR were designated as core basal, those with pathologic criteria were designated as path-basal, and those designated according to molecular profiling (PAM50) were designated as PAM50 BL.9 The non-core BL carcinomas may also be designated as 5-marker negative panel (5NP). In this study, only 13/116 (11 %) were defined as BL by all three modalities: it is evident that even the manner in which BL carcinomas are defined is problematic. The path–basal group had a significant decrease in nodal metastases, while the highest risk for death was in those immunohistochemically defined ‘core–basal’ TNBC. The path non-basal group included carcinomas that could only be designated as not otherwise specified (NOS). This latter group is associated with a higher risk of lymphovascular invasion and nodal metastases. BLBC, in contrast to normal breast basal or myoepithelial cells, expresses cytokeratins 8 and 18. This calls into question the initial implications of the microarray-based studies of breast cancers that suggest that BL cancers originate from basal myoepithelial cells. They may rather be derived from luminal progenitors.