Elsevier

The Lancet Oncology

Volume 8, Issue 3, March 2007, Pages 235-244
The Lancet Oncology

Review
Triple-negative breast cancer: therapeutic options

https://doi.org/10.1016/S1470-2045(07)70074-8Get rights and content

Summary

Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.

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

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.

References (77)

  • F Kamangar et al.

    Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world

    J Clin Oncol

    (2006)
  • DA Berry et al.

    Effect of screening and adjuvant therapy on mortality from breast cancer

    N Engl J Med

    (2005)
  • Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

    Lancet

    (2005)
  • G Konecny et al.

    Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer

    J Natl Cancer Inst

    (2003)
  • DJ Slamon et al.

    Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

    Science

    (1989)
  • CM Perou et al.

    Molecular portraits of human breast tumours

    Nature

    (2000)
  • T Sorlie et al.

    Repeated observation of breast tumor subtypes in independent gene expression data sets

    Proc Natl Acad Sci USA

    (2003)
  • T Sorlie et al.

    Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

    Proc Natl Acad Sci USA

    (2001)
  • C Sotiriou et al.

    Breast cancer classification and prognosis based on gene expression profiles from a population-based study

    Proc Natl Acad Sci USA

    (2003)
  • LJ van't Veer et al.

    Gene expression profiling predicts clinical outcome of breast cancer

    Nature

    (2002)
  • TO Nielsen et al.

    Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma

    Clin Cancer Res

    (2004)
  • RE Jimenez et al.

    Centrally necrotizing carcinomas of the breast: a distinct histologic subtype with aggressive clinical behavior

    Am J Surg Pathol

    (2001)
  • C Jones et al.

    CGH analysis of ductal carcinoma of the breast with basaloid/myoepithelial cell differentiation

    Br J Cancer

    (2001)
  • DM Abd El-Rehim et al.

    High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses

    Int J Cancer

    (2005)
  • DM Abd El-Rehim et al.

    Expression of luminal and basal cytokeratins in human breast carcinoma

    J Pathol

    (2004)
  • J Lamovec et al.

    Adenoid cystic carcinoma of the breast: a histologic, cytologic, and immunohistochemical study

    Semin Diagn Pathol

    (1989)
  • WD Foulkes et al.

    The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer

    Cancer Res

    (2004)
  • LA Carey et al.

    Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study

    JAMA

    (2006)
  • ML Asselin-Labat et al.

    Steroid hormone receptor status of mouse mammary stem cells

    J Natl Cancer Inst

    (2006)
  • KE Sleeman et al.

    CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells

    Breast Cancer Res

    (2006)
  • S Banerjee et al.

    Basal-like breast carcinomas: clinical outcome and response to chemotherapy

    J Clin Pathol

    (2006)
  • CR Osbourne et al.

    Clinical and pathological characterization of basal-like breast cancer

    Breast Cancer Res Treat

    (2005)
  • SM Rodriguez-Pinilla et al.

    Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas

    Clin Cancer Res

    (2006)
  • H Tsuda et al.

    Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases

    Am J Surg Pathol

    (2000)
  • Olopade OI, Ikpatt F, Perou CM. Intrinsic Gene Expression” subtypes correlated with grade and morphometric parameters...
  • Z Hu et al.

    The molecular portraits of breast tumors are conserved across microarray platforms

    BMC Genomics

    (2006)
  • A Bergamaschi et al.

    Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer

    Genes Chromosomes Cancer

    (2006)
  • R Callahan et al.

    Mutations in human breast cancer: an overview

    J Natl Cancer Inst

    (1989)
  • Cited by (0)

    View full text