Dissecting the Heterogeneity of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

“…Within-tumor clonal heterogeneity and variable clonal composition of different metastatic lesions provide a simple explanation for this clinical phenomenon and is supported by recent results from tumor sequencing of metastatic sites and matching primary tumors. Clonal selection in response to therapy has also been demonstrated in several different cancer types and provides explanation for the development of treatment resistance over time [37,[39][40][41]. The evolutionary relatedness of primary tumors and multiple metastases from the same patient suggests multiple different ways that metastasis can arise (Fig.…”

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

“…Triple-negative breast cancers (TNBC) account for 15% to 20% of all breast cancer cases and are defined by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. TNBC prognosis is poor and chemotherapy remains the sole therapeutic option (1). No targeted therapy is available for TNBC due to the lack of identified molecular targets in most of these cancers.…”

miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes

“…Although most TNBC respond to cytotoxic platinum/taxane-containing regimens, they are prone to recur, metastasize and become resistant to chemotherapy (Foulkes et al, 2010;Metzger-Filho et al, 2012). TNBCs are the breast cancer subtype most enriched for poorly differentiated CD44 + CD24 low/-ESA + tumor-initiating cells (T-ICs), sometimes called cancer stem cells, cells thought to be responsible not just for tumor initiation, but also for metastasis and resistance to chemotherapy (Al-Hajj et al, 2003;Keller et al, 2012).…”