What is triple-negative breast cancer?
Introduction
In 2007, 1.3 million women worldwide were diagnosed and 465,000 died from breast cancer making this the most common cancer in women and the leading cause of death.1 Though impressive, these statistics treat breast cancer as a homogeneous entity, which we increasingly recognise as inaccurate. Gene expression studies have identified several major subtypes of breast cancer2: the luminal subtypes, which typically express hormone receptor-related genes, and two hormone receptor-negative subtypes – the human epidermal growth factor receptor 2 (HER2) positive/oestrogen receptor (ER) negative subtype and the basal-like subtype. The subtypes vary in prognosis, with worse outcomes traditionally seen among the two hormone receptor-negative subgroups compared with the luminal subgroups3, 4, 5; however, improvements in chemotherapy, endocrine therapy and HER2-targeted therapy may change the prognostic landscape of breast cancer.
A subtype of particular interest is the basal-like breast cancer BBC. In population-based studies, this subtype comprises approximately 15–20% of breast cancers.6, 7, 8 In research studies, BBC has been reproducibly identified using gene expression methods4, 5 and immunohistochemistry,9, 10, 11 however, a validated method to identify BBC and other intrinsic subtypes of breast cancer for clinical use does not exist. In arrays, BBCs are characterised by low expression of ER-related genes and HER2-related genes; for this reason in clinical specimens they are usually ER-negative, progesterone receptor (PR) PR-negative and lack HER2 overexpression. This is called the ‘triple-negative’ phenotype.
Since triple-negative breast cancer is resistant to our current HER2-targeted therapies such as trastuzumab, and hormonal therapies such as tamoxifen and aromatase inhibitors, chemotherapy is the mainstay of treatment. This lack of targeted therapies has intensified the interest in this group of patients. This review will focus on the definition and features of triple-negative breast cancer, current treatment strategies and future directions for treatment.
Section snippets
Nomenclature
As mentioned above, most triple-negative breast cancers cluster with the BBC,10 however, these are not synonyms. ‘Triple negative’ is a term based upon clinical assays for ER, PR and HER2, while ‘basal-like’ is a molecular phenotype. The ‘basal-cell phenotype’ was first described by Wetzels et al. by using immunohistochemical markers to identify cytokeratins in breast tumours that normally were found only in the cell layer lying closest to the basement membrane of the mammary gland epithelium.12
Molecular features of triple-negative breast cancer
‘Unsupervised’ (heedless of clinical characteristics or outcome) gene expression array profiling studies on breast tumours have allowed breast cancers to be clustered according to their intrinsic gene expression patterns, revealing at least five intrinsic subtypes2, 3, 4, 5: luminal A and B, HER2+/ER-negative, normal breast-like, basal-like and potentially a ‘claudin-low’ subtype.21 These breast cancer subtypes are highly reproducible,3, 4, 5 persist before and after therapy, are concordant
Clinical features and risk factors
Triple-negative tumours typically have a higher histologic grade, elevated mitotic count, scant stromal content, central necrosis, pushing margins of invasion, a stromal lymphocytic response and multiple apoptotic cells27, 46; histologically they are largely ductal,6 but several unusual histologies are also overrepresented, including metaplastic,27, 47, 48 atypical or typical medullary,27, 49 or adenoid cystic carcinomas.50 A case series evaluating 65 metaplastic breast cancers by
BRCA 1 and basal breast cancer
BRCA1-associated breast cancers are mostly basal-like and triple negative4, 58 and express basal markers such as cytokeratins 5, 14, 17, and EGFR.59 Efforts to link sporadic (occurring in women without germline BRCA1 mutations) BBC with dysfunction of the BRCA1 pathway are ongoing.36, 60 While BRCA1 methylation and localisation appear similar across subtypes,60, 61 in one study BRCA1 mRNA was lower in BBC than in matched controls, and ID4, a downregulator of BRCA1, was expressed nine times more
Prognosis
BBC has molecular characteristics predictive of a poor prognosis. In one study comparing intrinsic subtypes with prognostic profiles in 53 patients with BBC, all had high Recurrence Scores, all had poor 70-gene profiles, 50 had activated wound response signatures and 42 had poor two-gene ratio signatures.62 The initial studies examining outcome by intrinsic subtype uniformly found a poor prognosis in BBC.3, 5 In population-based studies, the triple-negative phenotype demonstrated reduced breast
Therapy
Since there is no role for hormonal or HER2-targeted agents, the primary adjuvant therapy for triple-negative breast cancer is chemotherapy. As previously noted, these tumours respond to anthracycline- and anthracycline/taxane-based regimens; however, they have a high risk of relapse. Several promising avenues of improving our treatment armamentarium are in investigation (Table 3). The association of BBC with BRCA1 mutation carriers raises other chemotherapeutic possibilities. Tumours with
Conclusion
Triple-negative breast cancers mostly comprise the basal-like molecular subtype of breast cancer, which has distinctive clinical and pathological features. While triple-negative breast cancers do not necessarily present at later stages, in most datasets they have worse survival than the more common luminal subtype of breast cancer and have no known targeted agents, making chemotherapy the primary adjuvant and metastatic modality of treatment. They have unique risk factors such as an association
Conflict of interest statement
Consultant/Advisory (unpaid)
Bristol Myers Squibb
Sanofi–Aventis
Genentech
GSK
Pfizer
Speaker’s Bureau (unpaid)
Pfizer
Sanofi–Aventis
Research funding (to UNC)
Genentech
GSK
BMS
Boehringer–Ingelheim
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