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Triple?negative breast cancer therapy: Current and future perspectives (Review).

ABSTRACT: Triple?negative breast cancer (TNBC) accounts for 10?15% of all breast cancer cases. TNBCs lack estrogen and progesterone receptors and express low levels of HER2, and therefore do not respond to hormonal or anti?HER2 therapies. TNBC is a particularly aggressive form of breast cancer that generally displays poorer prognosis compared to other breast cancer subtypes. TNBC is chemotherapy sensitive, and this treatment remains the standard of care despite its limited benefit. Recent advances with novel agents have been made for specific subgroups with PD?L1+ tumors or germline Brca?mutated tumors. However, only a fraction of these patients responds to immune checkpoint or PARP inhibitors and even those who do respond often develop resistance and relapse. Various new agents and combination strategies have been explored to further understand molecular and immunological aspects of TNBC. In this review, we discuss clinical trials in the management of TNBC as well as perspectives for potential future treatments.

SUBMITTER: Won KA

PROVIDER: S-EPMC7646583 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Triple‑negative breast cancer therapy: Current and future perspectives (Review).

Won Kwang-Ai KA Spruck Charles C

International journal of oncology 20201016 6

Triple‑negative breast cancer (TNBC) accounts for 10‑15% of all breast cancer cases. TNBCs lack estrogen and progesterone receptors and express low levels of HER2, and therefore do not respond to hormonal or anti‑HER2 therapies. TNBC is a particularly aggressive form of breast cancer that generally displays poorer prognosis compared to other breast cancer subtypes. TNBC is chemotherapy sensitive, and this treatment remains the standard of care despite its limited benefit. Recent advances with no ...[more]

PMID: 33174058

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Project description:Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer-olaparib and talazoparib-based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

Project description:Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

Dataset Information

Triple?negative breast cancer therapy: Current and future perspectives (Review).

Publications

Triple‑negative breast cancer therapy: Current and future perspectives (Review).

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