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Immune Checkpoint Inhibition for Triple-Negative Breast Cancer: Current Landscape and Future Perspectives.

ABSTRACT: Triple-negative breast cancer (TNBC) is characterized by the lack of clinically significant levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the aggressive nature and the emergence of resistance to chemotherapeutic drugs, patients with TNBC have a worse prognosis than other subtypes of breast cancer. Currently, immunotherapy using checkpoint blockade has been shown to produce unprecedented rates of long-lasting responses in patients with a variety of cancers. Although breast tumors, in general, are not highly immunogenic, TNBC has a higher level of lymphocyte infiltration, suggesting that TNBC patients may be more responsive to immunotherapy. The identification/characterization of immune checkpoint molecules, i.e., programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PDL1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), represents a major advancement in the field of cancer immunotherapy. These molecules function to suppress signals downstream of T cell receptor (TCR) activation, leading to elimination of cytotoxic T lymphocytes (CTLs) and suppression of anti-tumor immunity. For TNBC, which has not seen substantial advances in clinical management for decades, immune checkpoint inhibition offers the opportunity of durable response and potential long-term benefit. In clinical investigations, immune checkpoint inhibition has yielded promising results in patients with early-stage as well as advanced TNBC. This review summarizes the recent development of immune checkpoint inhibition in TNBC, focusing on humanized antibodies targeting the PD1/PDL1 and the CTLA4 pathways.

SUBMITTER: Yi H

PROVIDER: S-EPMC8170306 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient's own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.

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.

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Immune Checkpoint Inhibition for Triple-Negative Breast Cancer: Current Landscape and Future Perspectives.

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