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16-11-2016 | Triple-negative breast cancer | Article

Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants

Fresia Pareja, Felipe C Geyer, Caterina Marchiò, Kathleen A Burke, Britta Weigelt, Jorge S Reis-Filho


Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12–17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Nonetheless, TNBC has been shown to constitute a vastly heterogeneous disease encompassing a wide spectrum of entities with marked genetic, transcriptional, histological and clinical differences. Although most TNBCs are high-grade tumors, there are well-characterized low-grade TNBCs that have an indolent clinical course, whose natural history, molecular features and optimal therapy vastly differ from those of high-grade TNBCs. Secretory and adenoid cystic carcinomas are two histologic types of TNBCs underpinned by specific fusion genes; these tumors have an indolent clinical behavior and lack all of the cardinal molecular features of high-grade triple-negative disease. Recent studies of rare entities, including lesions once believed to constitute mere benign breast disease (e.g., microglandular adenosis), have resulted in the identification of potential precursors of TNBC and suggested the existence of a family of low-grade triple-negative lesions that, despite having low-grade morphology and indolent clinical behavior, have been shown to harbor the complex genomic landscape of common forms of TNBC, and may progress to high-grade disease. In this review, we describe the heterogeneity of TNBC and focus on the histologic and molecular features of low-grade forms of TNBC. Germane to addressing the challenges posed by the so-called triple-negative disease is the realization that TNBC is merely a descriptive term, and that low-grade types of TNBC may be driven by distinct sets of genetic alterations.

npj Breast Cancer 2016;2:16036. doi:10.1038/npjbcancer.2016.36

Triple-negative (TN) breast cancers (TNBCs), defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), account for 12–17% of breast cancers.1 TNBCs have been shown to have a relatively aggressive clinical behavior, a high prevalence in women of Hispanic and African descent, an earlier age of presentation2 and a significant association with BRCA1 germline mutations.1 As a group, TNBCs display a high risk of metastasis and death within 5 years after diagnosis.3 Nonetheless, TNBC is vastly heterogeneous and best considered as an umbrella term, encompassing a wide spectrum of entities with marked genetic, transcriptional, histological, and clinical differences.4 Although most TNBCs are of high grade and do display a relatively aggressive clinical behavior, there are forms of low-grade TN disease, which have been shown to have a more indolent behavior (Figure 1).5,6,7 In addition, recent studies have brought forth the existence of lesions initially thought to be mere benign breast conditions that likely constitute precursors of TNBCs.8,9

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