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

Abstract

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.

Figure 1

The spectrum of histologic subtypes of TNBCs and a non-obligate precursor of TNBC. (a) High-grade invasive ductal carcinoma of no special type, (b) low-grade adenoid cystic carcinoma, (c) low-grade acinic cell carcinoma, (d) microglandular adenosis, (e) low-grade metaplastic adenosquamous carcinoma, (f) high-grade apocrine carcinoma, (g) high-grade metaplastic spindle cell carcinoma, (h) high-grade metaplastic squamous cell carcinoma, and (i) high-grade carcinoma with medullary features. TNBC, triple-negative breast cancer.

Figure 2

Somatic mutations affecting cancer genes in TNBCs from The Cancer Genome Atlas (TCGA). Bars indicate the frequency of somatic mutations affecting the 50 cancer genes most frequently mutated in TNBCs, based on a reanalysis of the 77 TNBCs from TCGA. Cancer genes are defined as per the cancer gene lists described by Kandoth et al. (127 significantly mutated genes), the Cancer Gene Census, or Lawrence et al. (Cancer5000-S gene set). TNBC, triple-negative breast cancer.

Figure 3

Comparative analysis of molecular subclassification systems applied to TNBCs. (a) Prevalence of each subtype according to PAM50, Lehmann et al., and Burstein et al. (b) Comparison between the distinct classifications; Burstein et al. versus PAM50, Lehmann et al. versus PAM50, and Burstein et al. versus Lehmann et al. BL1, basal-like 1; BL2, basal-like 2; BLIA, basal-like immune-activated; BLIS, basal-like immunosuppressed; IM; immunomodulatory; LAR, luminal androgen receptor; LumA, luminal A; LumB, luminal B; M, mesenchymal; MES, mesenchymal; MSL, mesenchymal stem-like; TNBC, triple-negative breast cancer; UNC, unclassified.

Figure 4

Progression from low- to high-grade within the proposed low-grade triple-negative breast neoplasia family and salivary gland-like tumors of the breast. (a) Representative low-power magnification of a high-grade invasive carcinoma of no special type (left) arising in microglandular adenosis (right). (b) Representative high-power magnification of microglandular adenosis with (c) diffuse immunohistochemical expression of lysozyme, a marker of serous acinar differentiation. (d) Representative high-power magnification of associated high-grade invasive carcinoma of no special type, with (e) focal lysozyme expression by immunohistochemistry. (f) Representative low-power magnification of a high-grade invasive carcinoma of no special type (left) arising in an adenoid cystic carcinoma (right). (g) Representative high-power magnification of a high-grade invasive carcinoma of no special type with (h) high Ki67 proliferation rate. (i) Representative high-power magnification of associated adenoid cystic carcinoma with (j) low Ki67 proliferation rate.

Figure 5

Hypothetical model of potential evolutionary paths of TNBCs. We propose that in addition to high-grade TNBCs, two subtypes of low-grade TNBCs can be identified on the basis of their distinctive histology and molecular features: salivary gland-like tumors of the breast, which are underpinned by specific/pathognomonic genetic alterations, and the proposed low-grade breast triple-negative neoplasia family, whose tumors display genomic profiles similar to those of conventional high-grade TNBCs. Please note that both low-grade subgroups can progress to high-grade TNBCs, however, the high-grade TNBCs arising in salivary gland-like tumors also differ from conventional TNBCs at the genetic level and harbor the same genetic aberrations identified in their respective low-grade counterparts. TNBC, triple-negative breast cancer.