Relevant articles were identified by searches of MEDLINE using the terms: “basal” or “triple negative” or “BRCAness” with the words “cancer” and “breast”. Reference lists, abstract books, and CDs from conferences were also manually searched. Only articles published in English were used.
ReviewTriple-negative breast cancer: therapeutic options
Introduction
Breast cancer is a common disease and its incidence is increasing worldwide.1 However, during the past three decades,2 the mortality rate in developed countries has declined as a result of a range of measures, including implementation of screening,3 improvements in the local management of early breast cancer,4 and, most importantly, the introduction of adjuvant systemic treatments.5 With targeted treatments gradually emerging, further improvements in outcome of at least some subgroups of breast cancer, will probably take place in the near future.
Targeted treatments consist of strategies that are directed at a distinct molecular target that differentiates (usually imperfectly) malignant from benign cells, and which is important in the growth and progression of the cancer. Most targeted treatments have been directed against a nuclear or surface receptor, as exemplified by tamoxifen and trastuzumab, respectively. By contrast, cytotoxic treatment is not classified as a targeted treatment because many of its specific targets have not been defined.
Hormone receptor (ie, oestrogen receptor [ER] or progesterone receptor [PgR])-positive breast cancer and ERBB2-positive breast cancer currently account for 75–80% and 15–20% of breast cancer cases, respectively,6, 7 with about half of ERBB2-positive cases coexpressing hormone receptors.6 The remaining 10–15% of breast cancers are in a so-called receptor-negative or triple-negative category, as defined by absent expression of these three proteins. As a result, this aggressive disease entity is resistant to existing targeted treatments, namely trastuzumab and hormonal treatments, and is an increasingly feared diagnosis among patients with breast cancer. The pathways that drive proliferation of these tumours are still poorly understood; however, once they have been elucidated, targeted agents can be developed, which could result in a better outcome for patients with this type of cancer. The features of triple-negative breast cancer described in this review, in relation to possible therapeutic targets, are summarised in figure 1. Potential targets for treatment include: surface receptors, such as epidermal growth factor receptor (EGFR) or c-KIT; protein kinase components of the mitogen activated protein (MAP)-kinase pathway; protein kinase components of the protein kinase B (Akt) pathway; induction of DNA damage by specific chemotherapy agents—these cancers might be more sensitive to agents that cause interstrand and double-stranded breaks; and inhibition of already defective DNA repair—eg, by poly ADP-ribose polymerase 1 (PARP1) inhibition.
Section snippets
Definition of triple-negative and basal-like breast cancer
Until recently, breast cancer was subclassified on the basis of cellular morphology and the presence of several receptors, namely ER, PgR, and the ERBB2, identified by immunohistochemical staining. Such classification has proved useful in terms of predicting prognosis and guiding treatment recommendations. Array gene-expression profiling has also allowed breast cancers to be assessed in terms of the expression of genes; ie, a so-called expression signature. In their landmark study, Perou and
Pathological features
Triple-negative breast cancer is a recent term and refers to cancers that do not express ER, PgR, and ERBB2 receptors. The features of this subgroup roughly equate to those of the basal-like subgroup of breast cancers, which have been extensively described in published work. Basal-like cancers are identified in most studies by immunohistochemical staining for the expression of CK 5/6, and characteristic morphology consisting of high proliferative rate, central necrosis, and a pushing border.13
Treatment implications of BRCA1 dysfunction
The data summarised above suggests that the molecular defects that give rise to BRCA1-associated breast cancers also occur in triple-negative cancers, and that a shared therapeutic approach could be appropriate. There is increasing evidence that the DNA-repair defects characteristic of BRCA1-related cancers, especially defective homologous recombination, confer sensitivity to certain systemic agents,47, 48 which could be relevant to the treatment of triple-negative breast cancer. In vitro
Current treatment for triple-negative breast cancers
There is currently no specific systemic regimen recommended for the treatment of triple-negative breast cancers, and little data on which to base treatment selection (table 3). Pathological and molecular determinants of the chemosensitivity of breast cancers in general have been extensively explored through neoadjuvant studies. There are several features inherent to basal-like cancers that have consistently been shown to be associated with clinical and pathological responsiveness to neoadjuvant
Treatment directed against proliferative pathways
Proliferative signals in the form of cytokines, hormones, or growth factors activate receptors, which trigger intracellular signalling cascades that ultimately communicate with the nucleolus to bring about changes in gene expression. These consist of protein kinases which phosphorylate target proteins, thereby controlling their enzyme activity, interactions with other molecules, cellular location, and resistance to degradation. Many components of these proliferative pathways are overexpressed
Future directions
Clearly, the testing (and indeed therapeutic administration) of these new drugs must be appropriately targeted. For an agent to be effective, it should block a non-redundant, abnormal pathway, and, in some cases, effectiveness will depend on the presence of a particular mutation. However, most studies have not applied rigorous molecular selection for the target abnormality and many have not collected tumour specimens to measure correlations between response and baseline features and
Conclusion
A large number of targeted anticancer agents are currently emerging, and some of these could be applicable to the treatment of triple-negative breast cancers. At the same time, breast cancer subtypes are being defined in far greater detail by molecular profiling. In theory, it should be possible to match agents (mechanisms) to the targets present in a given cancer type. In reality the situation will be much more complex, with sensitivity to drugs depending not only on the level of expression or
Search strategy and selection criteria
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