scholarly journals Checkpoint Inhibitors and Their Application in Breast Cancer

Breast Care ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Davide Bedognetti ◽  
Cristina Maccalli ◽  
Salha B.J. Al Bader ◽  
Francesco M. Marincola ◽  
Barbara Seliger
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Immune Surveillance ◽  
Significant Proportion ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Breast Cancers ◽  
Inhibitory Molecules

Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

scholarly journals Checkpoint Inhibitors in Breast Cancer - Current Status and Future Directions

Breast Care ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Joachim Bischoff
Keyword(s):  
Breast Cancer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Death Receptor ◽  
Target Population ◽  
Current Status ◽  
Immune Checkpoints ◽  
Breast Cancer Patients

Antineoplastic agents directly targeting tumor cells have represented the major strategy of systemic anticancer therapy for many years. Nevertheless, overcoming resistance mechanisms remains a great challenge because treatment options are limited in many cases. From this point of view, immunotherapeutic approaches seem promising in a broad spectrum of solid tumors. These include in particular the currently available inhibitors directed against immune checkpoints leading to a significant T-cell activation. To date, the programmed death receptor 1 (PD-1) and its ligand are the most prominent targets in this context. However, the role of checkpoint inhibitors in the treatment of breast cancer is still being debated, and the main focus is on triple-negative breast cancer patients as a target population in many ongoing trials. Moreover, the potential superiority of combinations with other anticancer drugs such as cytotoxics and targeted agents will be discussed.

scholarly journals Next generation of immune checkpoint inhibitors and beyond

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Julian A. Marin-Acevedo ◽  
ErinMarie O. Kimbrough ◽  
Yanyan Lou
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Immune Checkpoints ◽  
Host Immune System ◽  
Immune Recognition

AbstractThe immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.

scholarly journals Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 628 ◽  
Author(s):  
Sebastian Chrétien ◽  
Ioannis Zerdes ◽  
Jonas Bergh ◽  
Alexios Matikas ◽  
Theodoros Foukakis
Keyword(s):  
Breast Cancer ◽  
Cancer Immunotherapy ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoints ◽  
Cancer Subtypes ◽  
Host Interactions ◽  
Inhibitory Molecules ◽  
The Cost ◽  
Cell Death Protein ◽  
Triple Negative Subtype

Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor – host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.

scholarly journals Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1949
Author(s):  
Yawen Dong ◽  
Jeffrey Sum Lung Wong ◽  
Ryohichi Sugimura ◽  
Ka-On Lam ◽  
Bryan Li ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Advanced Hcc ◽  
Oncogenic Pathways ◽  
Vegf Pathway ◽  
And Function ◽  
Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

scholarly journals The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jia-Wern Pan ◽  
Muhammad Mamduh Ahmad Zabidi ◽  
Pei-Sze Ng ◽  
Mei-Yee Meng ◽  
Siti Norhidayu Hasan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Checkpoint Inhibitors ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Breast Tumours ◽  
Different Populations ◽  
Caucasian Women ◽  
Molecular Landscape ◽  
Immune Score

AbstractMolecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

scholarly journals Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 636 ◽  
Author(s):  
Regina Padmanabhan ◽  
Hadeel Shafeeq Kheraldine ◽  
Nader Meskin ◽  
Semir Vranic ◽  
Ala-Eddin Al Moustafa
Keyword(s):  
Breast Cancer ◽  
Mathematical Models ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Breast Cancers ◽  
Treatment Protocols ◽  
Cancer Subtypes ◽  
Cancer Management ◽  
Her2 Breast Cancer ◽  
Programmed Death

Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

HER-2-Amplified Breast Cancer

2018 ◽  
Author(s):  
Zahraa Al-Hilli ◽  
Judy C Boughey
Keyword(s):  
Breast Cancer ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Breast Cancers ◽  
Aggressive Disease ◽  
Node Positive Disease ◽  
Her 2 ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Amplification of the human epidermal growth factor receptor–2 (HER-2) gene is found in approximately 15 to 30% of breast cancers. Historically, HER-2 overexpression has been associated with aggressive disease and a poor prognosis. However, the use of targeted anti-HER2 therapy has revolutionized the treatment of HER-2-positive disease, and the use of the monoclonal antibody trastuzumab in combination with chemotherapy is now standard of care for tumors greater than 1 cm in size and in node-positive disease. More recently, the value of dual-agent anti-HER-2 therapy has been demonstrated in large clinical trials. This review provides an overview of HER-2-positive breast cancer, its molecular basis, methods of identification, and treatment options and strategies. This review contains 2 figures and 70 references Key words: anti-HER-2 therapy, breast cancer, HER-2-positive breast cancer, HER-2 resistance, lapatinib, neoadjuvant chemotherapy, pertuzumab, small HER-2-positive breast cancer, trastuzumab

scholarly journals Immune Checkpoint Inhibitors for Brain Metastases: A Primer for Neurosurgeons

Neurosurgery ◽  
2020 ◽  
Vol 87 (3) ◽  
pp. E281-E288
Author(s):  
Elisa Aquilanti ◽  
Priscilla K Brastianos
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Nonsmall Cell Lung Cancer ◽  
Immune Recognition ◽  
Therapeutic Modalities ◽  
Programmed Death 1

Abstract Immune checkpoint inhibitors enhance immune recognition of tumors by interfering with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD1) pathways. In the past decade, these agents brought significant improvements to the prognostic outlook of patients with metastatic cancers. Recent data from retrospective analyses and a few prospective studies suggest that checkpoint inhibitors have activity against brain metastases from melanoma and nonsmall cell lung cancer, as single agents or in combination with radiotherapy. Some studies reported intracranial response rates that were comparable with systemic ones. In this review, we provide a comprehensive summary of clinical data supporting the use of anti-CTLA4 and anti-PD1 agents in brain metastases. We also touch upon specific considerations on the assessment of intracranial responses in patients and immunotherapy-specific toxicities. We conclude that a subset of patients with brain metastases benefit from the addition of checkpoint inhibitors to standard of care therapeutic modalities, including radiotherapy and surgery.

scholarly journals Breast Imaging During Pregnancy and Lactation

2019 ◽  
Vol 1 (4) ◽  
pp. 342-351
Author(s):  
Lisa Abramson ◽  
Lindsey Massaro ◽  
J Jaime Alberty-Oller ◽  
Amy Melsaether
Keyword(s):  
Breast Cancer ◽  
Breast Imaging ◽  
Treatment Options ◽  
Nipple Discharge ◽  
Cancer Staging ◽  
Imaging Features ◽  
Breast Cancers ◽  
Bloody Nipple Discharge ◽  
Breast Cancer Staging ◽  
Pregnancy And Lactation

Abstract Breast imaging during pregnancy and lactation is important in order to avoid delays in the diagnosis and treatment of pregnancy-associated breast cancers. Radiologists have an opportunity to improve breast cancer detection by becoming familiar with appropriate breast imaging and providing recommendations to women and their referring physicians. Importantly, during pregnancy and lactation, both screening and diagnostic breast imaging can be safely performed. Here we describe when and how to screen, how to work up palpable masses, and evaluate bloody nipple discharge. The imaging features of common findings in the breasts of pregnant and lactating women are also reviewed. Finally, we address breast cancer staging and provide a brief primer on treatment options for pregnancy-associated breast cancers.

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