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

Practical Implications of Basal-like and Triple-negative Breast Cancers

As outlined above, a diagnosis of triple-negative breast cancer has direct clinical implications. Given that these tumors lack expression of hormone receptors and lack HER2 protein overexpression and gene amplification, chemotherapy is the only modality of adjuvant systemic therapy currently available for patients with triple-negative disease. Furthermore, the current prognostic algorithms to define which patients should receive chemotherapy may not work optimally for patients with triple-negative breast cancer, given that the impact of size on the outcome of these patients appears to be significantly attenuated.[136,137]

At present, use of the term 'basal-like breast cancer' in diagnostic surgical pathology reports does not appear to be justified, as it does not lead to any direct clinical action. In fact, given the variations in definition of basal-like breast cancers, such a diagnosis may cause clinical confusion. For instance, according to some definitions, a breast cancer showing ER expression and expression of CK 5/6 or CK 14 would be classified as being of basal-like phenotype. However, there are currently no data to indicate that patients with ER+ breast cancers that show basal cytokeratin expression should be managed any differently than ER+, basal cytokeratin-negative breast cancers of equivalent size and stage (ie, with hormonal therapy, with or without chemotherapy). Likewise, patients with an HER2+ breast cancer showing a basal-like phenotype would still receive trastuzumab and chemotherapy, similar to other patients with HER2+ breast cancer. Thus, given that the term basal-like per se does not impact on clinical decision making, the inclusion of the term 'basal-like breast cancer' in pathology reports at present would be best avoided. However, it might be argued that subclassification of triple-negative tumors into subtypes using the Nielsen definition[17] is of prognostic significance and is associated with specific patterns of metastatic dissemination. If one were to use such an approach, to ensure consistency it is recommended that tumors that express more than 1% CK5/6 or EGFR should be considered positive for these markers. There are also data to suggest that the CK5 antibody is superior to the CK5/6 antibody for identification of this type of basal cytokeratin.[138] The role of CK14 in the subclassification of triple-negative cancers into basal-like and non-basal-like phenotypes is uncertain.

Perhaps more important than identifying the basal-like subgroup within triple-negative breast cancers is the identification of subgroups of triple-negative disease that are sensitive to specific systemic therapy regimens. Several groups are currently developing biomarkers for the identification of the subgroup of triple-negative cancers with dysfunctional homologous recombination DNA repair, given that these tumors are likely to show an exquisite sensitivity to PARP inhibitors. Furthermore, other promising targets for subgroups of basal-like cancers have recently emerged (eg, FGFR2, TRAIL, antiangiogenic agents). Therefore, the question that is germane for the management of breast cancer patients is the identification of predictive biomarkers to substratify patients with triple-negative cancers into groups that can be managed more efficaciously with specific systemic therapies.

It is also important to remember that the lack of overlap between categories identified by gene expression and immunohistochemistry methods is not restricted to basal-like and triple-negative tumors. Up to 25% of clinically ER+ tumors are classified as of nonluminal subtype by gene expression methods.[11] Similarly, nearly a third of the clinically HER2+ (FISH and/or IHC) are not classified as belonging to HER2-enriched category.[11] At least for now, treatment decisions are made on the basis of clinical (and not gene expression) assays.

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