Triple Negative Breast Cancer—Review of Current and Emerging Therapeutic Strategies

Abstract

T riple negative breast cancer (TNBC) is associated with a poor prognosis compared to other types of breast cancer. The classification of 'triple negative' is not one homogenous tumor type, but rather is made up of multiple molecularly and biologically diverse tumor subtypes. At present, no approved targeted therapy exists and the standard remains cytotoxic chemotherapy. The identification of TNBC subtypes has provided a basis for identifying possible targeted therapeutic options. In addition, the recognition that some TNBCs share characteristics similar to tumors arising in patients with germline BRCA mutations has led to consideration of DNA damaging agents as a potential treatment option. Multiple investigational approaches are also underway, including immune checkpoint inhibition, poly (ADP-ribose) polymerase inhibition, and androgen receptor blockage. The limited options available for systemic treatment of TNBC will hopefully expand as more is learned about the complex biology and molecular targets of this group of breast cancers. This review will discuss the biology of TNBC, current treatment options, and promising experimental strategies. KeywordsTriple negative, breast cancer, therapeutics 1 It is more common in African American women, younger women, and those with a germline BRCA1 mutation. Due to lack of ER, PR, and HER2 and the significant heterogeneity among TNBC, no approved targeted therapies exist and standard treatment remains cytotoxic chemotherapy. While response rates to chemotherapy in early stage disease are high, patients remain at high risk for relapse and prognosis remains inferior to other types of breast cancer. Subtyping and molecular characteristicsIn a seminal paper by Perou et al., gene expression profiling was used to categorize breast cancers into five molecular subtypes. The basal-like type is characterized by lack of ER, PR, and HER2 expression, expression of cytokeratins and EGFR, and a clinically more aggressive phenotype.2 This subtype overlaps with TNBC but the terms are not synonymous; in fact, about one fourth of TNBCs are not basal-like by gene expression, and some non-TNBCs are basal-like by molecular profiling (see Figure 1). 3,4 As more is discovered about the biology of TNBC, it has become clear that this category of breast cancer is not one homogeneous tumor type, but rather is made up of a group of molecularly diverse tumor subtypes. These subtypes have varying gene expression profiles, clinical characteristics, and responses to treatment. In an effort to translate the heterogeneity of TNBC into rational clinical design, Lehmann and colleagues further characterized TNBC into six distinct subtypes based on molecular profiles, each with unique drivers and clinical phenotypes. These subtypes include basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor(LAR).5 Each exhibited different sensitivities to therapeutic agents, both in cell line models and in some retrospective clinical trials...

Triple-Negative Breast Cancer

“…29 TNBCs have shown a higher response rate to neoadjuvant therapy compared with estrogen receptorepositive tumors. 30 However, residual disease in TNBC patients is associated with a poorer prognosis and shorter recurrence-free survival when compared with other types of breast cancer with residual disease. The lack of identification of significant genomic driver alterations in TNBC, and the degree of tumor cell heterogeneity, has limited a targeted approach to management.…”

Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy

“…Although defined in many aspects, TNBC is not homogenous, but represents several diverse molecular and clinical features and at least six distinct subtypes of TNBC can be considered [5]. Moreover, TNBC often displays molecular and clinical characteristics similar to DNA repair-associated breast cancer type 1 (BRCA1)-deficient breast cancer cases [6].…”

Recent advances in understanding breast cancer and emerging therapies with a focus on luminal and triple-negative breast cancer

“…Metastatic TNBC is highly heterogenic and, despite all the advances in the field of BC, remains an unmet medical need where few therapies besides the standard cytotoxic chemotherapy are available 41 . While sharing immunohistochemical characteristics, diverse molecular subtypes of TNBC have different gene expression profiles, clinical behavior, and response to treatment 42 . Lehmann et al .…”

“…41 highlight the intrinsic diversity of TNBC by using gene expression profiling. They subclassify TNBC into five categories, each exhibiting a different treatment sensitivity: (1) basal-like 1, which shows a higher sensitivity to platinum-based chemotherapy and DNA damage therapies; (2) basal-like 2, which is less sensitive to chemotherapy and is characterized by an upregulation of genes involved in the growth factor signaling pathway; (3) the immune group; (4) mesenchymal with a great response to PI3K pathway inhibitors; and (5) luminal androgen receptor (LAR), which may be more sensitive to androgen receptor (AR) antagonists and have a relative insensitivity to standard chemotherapy 42– 47 .…”