Emerging Drug Targets and Novel Therapeutic Strategies in Triple-Negative Breast Cancer
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Abstract
Triple-negative breast cancer (TNBC) is approximately 10–20% of all breast-cancer diagnoses and is a clinically aggressive, biologically heterogeneous phenotype that results as concomitant deficiency of estrogen receptor, progesterone receptor, and HER2 expression. In its turn, this molecular signature limits the number of targeted therapies and is associated with a dreadful prognosis and a high recurrence rate compared to other subtypes of breast-cancer. Traditionally, the management was based on systemic cytotoxic chemotherapy; however, over the last ten years, there has been an impressive advancement that completely changed the treatment environment of TNBC. Antibody-drug conjugate (ADC) has become an essential therapeutic breakthrough, which enables the delivery of highly potent cytotoxic compounds to malignant cells in a targeted manner. Newer drugs like Sacituzumab govitecan and trastuzumab deruxtecan have produced significant effects on progression-free and overall survival particularly in HER2-low TNBC. There has also been an improvement in PD-L1 positive early-stage and metastatic TNBC with immune checkpoint inhibitors (ICIs), especially pembrolizumab, and synergy of chemo therapeutic agents. Additionally, poly(ADP-ribose) polymerase (PARP) inhibitors, among them olaparib and talazoparib have shown strong efficacy in the population with germline BRCA1/2 mutations through synthetic lethality. New treatment paradigms that query PI3K/AKT axis, androgen receptor signalling and DNA-damage-response (DDR) signatures are currently in strict development in biomarker-selected cohorts. Active clinical trials are testing the rational combination approaches that involve ADCs, ICIs, and PARP inhibitors among other targeted therapies which are expected to overcome the resistance to therapeutic effects and to prolong the duration of response.
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