Biology and Management of Patients With Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared with other breast cancer subtypes. Because of the lack of approved targeted therapy, at present chemotherapy remains the mainstay of treatment for early and advanced disease. TNBC is enriched for germline BRCA mutation, providing a foundation for the use of this as a biomarker to identify patients suitable for treatment with DNA-damaging agents. Inherited and acquired defects in homologous recombination DNA repair, a phenotype termed "BRCAness," may be present in a large proportion of TNBC cases, making it an attractive selection and response biomarker for DNAdamaging therapy. Triple-negative breast cancer is a diverse entity for which additional subclassifications are needed.Increasing understanding of biologic heterogeneity of TNBC has provided insight into identifying potentially effective systemic therapies, including cytotoxic and targeted agents. Numerous experimental approaches are under way, and several encouraging drug classes, such as immune checkpoint inhibitors, poly(ADP-ribose) polymerase inhibitors, platinum agents, phosphatidylinositol-3-kinase pathway inhibitors, and androgen receptor inhibitors, are being investigated in TNBC. Molecular biomarker-based patient selection in early-phase trials has the potential to accelerate development of effective therapies for this aggressive breast cancer subtype. TNBC is a complex disease, and it is likely that several different targeted approaches will be needed to make meaningful strides in improving the outcomes. The Oncologist 2016;21:1050-1062Implications for Practice: Triple-negative breast cancer (TNBC) is an aggressive subtype that is associated with poor outcomes.This article reviews clinical features and discusses the molecular diversity of this unique subtype. Current treatment paradigms, the role ofgermline testing, and platinum agents in TNBC are reviewed. Results and observations from pertinent clinical trials with potential implications for patient management are summarized.This article also discusses the clinical development and ongoing clinical trials of novel promising therapeutic agents in TNBC.

Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

“…Triple-negative breast cancer has the worst prognosis of the histologic subtypes due to presenting at higher grade at diagnosis, increased recurrence risk following treatment, and shortened time to metastasis (27). The paradoxical observation that the molecular subtypes comprising these tumors also exhibit high levels of immune cell infiltration suggests that these infiltrating cells may have a deleterious impact on patient outcome.…”

“…Mice undergoing Treg depletion (DEREG mice) received i.p. injections of 1 μg DT in PBS on days -1, +1, +6, and +7 (27). Mice undergoing specific inhibition of p110δ PI3K were given drug (75 mg/kg PI-3065, once daily) or vehicle (0.5% methylcellulose with 0.2% Tween 80) by oral gavage from day +1 through the duration of the experiment (26).…”

The Position of Combination Chemotherapy with Mitomycin C and Methotrexate in the Treatment of Metastatic Breast Cancer - Especially Triple Negative Breast Cancer

“…While TN-breast cancer lacks an effective treatment such as those targeting hormonal receptors and HER2 [7], several key drugs have been developed and are promising treatments for this subtype of breast cancer. For example, platinum analogues such as carboplatin and cisplatin, which act directly and cross-link DNA, are effective treatments for TN-breast cancer, especially in patients with germline mutations of BRCA1/2 [8].…”

“…The platinum analogues have been shown to be effective in patients with MBC associated with germline BRCA1/2 mutations [25]. In addition, TN-breast cancers with acquired deficiency of BRCA1/2 function, which are referred to as 'BRCAness', also respond well to platinum analogues, because homologous recombination DNA repair is impaired in TN-breast cancer with BRCA mutations whether inherited or acquired [7]. Breast cancer cases with BRCAness also include some with sporadic breast cancers that share phenotypic characteristics with those associated with germline BRCA mutations, for example, due to low BRCA gene expression caused by DNA methylation of BRCA gene promoter regions [26,27].…”

“…We cannot as yet speculate as to which type of TN-breast cancer would respond well to MTX, because there are no studies using MTX as the only treatment for TN-breast cancer. Elucidating the association between FRA expression patterns and types of TN-breast cancer might provide clues for developing novel TN-MBC treatments [7,37].…”