Basal-like and Triple-negative Breast Cancers

A Critical Review With an Emphasis on The Implications for Pathologists and Oncologists

Sunil Badve; David J Dabbs; Stuart J Schnitt; Frederick L Baehner; Thomas Decker; Vincenzo Eusebi; Stephen B Fox; Shu Ichihara; Jocelyne Jacquemier; Sunil R Lakhani; José Palacios; Emad A Rakha; Andrea L Richardson; Fernando C Schmitt; Puay-Hoon Tan; Gary M Tse; Britta Weigelt; Ian O Ellis; Jorge S Reis-Filho

Disclosures

Mod Pathol. 2011;24(2):157-167. 

In This Article

What is a Basal-like Breast Cancer?

The characteristics of basal-like breast cancer have been extensively reviewed in the past 18 months.[10,14–16] It should be noted that there is still no internationally accepted definition for basal-like breast cancers and how best to define these tumors is a matter of controversy and ongoing debate. Some groups have used microarray-based expression profiling to define basal-like breast cancers, whereas others have used panels of immunohistochemical markers as surrogates. However, direct comparisons between the proposed immunohistochemical markers and the microarray-defined molecular subtypes are scarce.[17,18] Immunohistochemical marker panels that have been proposed to define basal-like breast cancers include: (1) lack of ER, PR, and HER2 expression ('triple-negative' immunophenotype); (2) expression of one or more high-molecular-weight/basal cytokeratins (CK5/6, CK14, and CK17); (3) lack of expression of ER and HER2 in conjunction with expression of CK5/6 and/or epidermal growth factor receptor (EGFR);[17] and (4) lack of expression of ER, PR, and HER2 in conjunction with expression of CK5/6 and/or EGFR.[19]

Despite the different definitions for basal-like breast cancers, it has been demonstrated that these tumors have distinctive clinical presentations,[20] histological features,[18,21] response to chemotherapy,[22–28] sites of distant relapse, and outcome.[7,9,29–31] In brief, basal-like tumors comprise a heterogeneous group that accounts for up to 15% of all breast cancers, affect younger patients, are more prevalent in African-American women, and often present as interval cancers. Histologically, the majority of basal-like breast cancers is of IDC-NST type, high histological grade, and characterized by exceptionally high mitotic indices, the presence of central necrotic or fibrotic zones, pushing borders, conspicuous lymphocytic infiltrate, and typical/atypical medullary features (Figure 1).[18,21,32] The similarity of these features with those of human papilloma virus-induced squamous cell carcinoma of the head and neck has led to the identification of the role of retinoblastoma gene (RB1) in these tumors.[33] However, not all basal-like cancers are of the IDC-NST type; the majority of medullary and atypical medullary,[4,34–36] metaplastic,[4,37,38] secretory,[39] myoepithelial, and adenoid cystic carcinomas[4,40] of the breast also show a basal-like phenotype.[5] More recently, a subgroup of lobular carcinomas has been shown to express high-molecular-weight cytokeratins,[41] however it remains to be determined whether these cases truly show a basal-like transcriptome. The majority of basal-like breast cancers lack or show low levels of ER and PR, lack HER2 protein overexpression and HER2 gene amplification, whereas they express genes and proteins usually found in 'basal'/myoepithelial cells of the normal breast including high-molecular-weight cytokeratins (5/6, 14 and 17),[17,19,21,42] P-cadherin,[43] caveolins 1 and 2,[44,45] nestin,[46]αB crystallin,[47,48] CD109,[49,50] and EGFR[17] and, in a minority of cases, harbor EGFR gene amplification[51] or aneusomy.[52] p53 immunohistochemical expression or TP53 gene mutations is observed in up to 85% of cases,[53,54] and alterations of the pRB and p16 G1/S cell-cycle checkpoint are remarkably prevalent in these cancers.[33,55] A recent study demonstrated that approximately 30% of basal-like breast cancers concurrently show lack of pRB expression, overexpression of p16 and p53 immunoreactivity (pRB−/p16+/p53+), whereas this profile was rarely seen in tumors of other molecular subtypes.[33] Basal-like cancers show remarkably high proliferation indices as defined by mitotic counting or by Ki67 labeling index.[26,33,56]

Figure 1.

The typical morphological features of triple-negative/basal-like cancer are those of a high-grade ductal carcinoma (Nottingham grade 3) associated with prominent lymphoid aggregates (a). It is not uncommon to observe extensive areas of necrosis (b) or central fibrosis. Cytologically, the tumor cells show marked nuclear pleomorphism and conspicuous mitotic activity (c). Prominent membranous expression of EGFR (d) and CK5 (e) is frequently noted.

Of interest, basal-like breast cancers, unlike 'basal'/myoepithelial cells of normal breast, almost uniformly express cytokeratins 8 and/or 18, calling into question the initial histogenetic implications of the microarray-based taxonomy of breast cancers that suggested that basal-like cancers would arise from basal/myoepithelial cells.[5,14] This has been emphasized in a recent study, which suggested that at least a subgroup of basal-like breast cancers may originate from luminal progenitors rather than basal/myoepithelial cells of the breast,[57] and confirmed by the results of conditional mouse models.[58] In this context, it is important to note that histogenesis and differentiation are two distinct processes although often mistakenly used as synonyms.

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