Abstract
Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.
Highlights
Triple-negative breast cancer (TNBC) is defined as a tumor lacking estrogen (ER) and progesterone (PR) receptor expression and human epidermal growth factor receptor 2 (HER2) overexpression/amplification
By in-silico analysis and western blotting, TNFSF13 expression was found to inversely correlate with the activity of the Akt-mammalian target of rapamycin (mTOR) pathway, which acts as a negative regulator of autophagy activity. Consistent with this finding, the pharmaceutical inhibition of autophagy activity significantly re-establishes the efficacy of PTX in TNFSF13-treated HCC1806 cells. These findings suggest that TNFSF13 promotes chemoresistance in TNBCs through autophagy initiation and that TNFSF13 overexpression accounts for a poor response to CT in TNBCs
TNBC is associated with the worst prognosis [2,4], and in spite of efforts performed in the last decades, no significant improvement in PFS and overall survival (OS) was obtained [225,226]
Summary
Triple-negative breast cancer (TNBC) is defined as a tumor lacking estrogen (ER) and progesterone (PR) receptor expression and human epidermal growth factor receptor 2 (HER2) overexpression/amplification. In TNBC patients, disease progression and recurrence typically occur within the first 3–5 years after diagnosis; brain and lung metastases are more common [2,4] This behavior is attributed to higher biological aggressiveness, including the emergence of resistance to chemotherapy (CT), which is the mainstay treatment in TNBC. A TNBC subgroup termed claudin-low molecular subtype was identified This subtype lacks basal markers and is enriched in stem cell and epithelial–mesenchymal transition (EMT). A further classification into four subtypes was made by Burstein et al.: androgen receptor (AR) positive, mesenchymal, basal-like immune sup-pressed, and basal-like immune activated [10] These subtypes might predict response to targeted therapy; they are not used in clinical practice, and cytotoxic chemotherapy remains the mainstay in TNBC treatment. Biomarkers helpful in predicting resistance to chemotherapy and drugs either currently recommended or potentially useful in chemoresistant TNBC are considered
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