scholarly journals Therapeutic Associations Comprising Anti-PD-1/PD-L1 in Breast Cancer: Clinical Challenges and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5999
Author(s):  
Fanny Ledys ◽  
Laura Kalfeist ◽  
Loick Galland ◽  
Emeric Limagne ◽  
Sylvain Ladoire
Keyword(s):  
Breast Cancer ◽  
Tumor Targeting ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Therapeutic Approaches ◽  
Cytotoxic Effects ◽  
Tumor Immune Microenvironment ◽  
Immunological Effects ◽  
Immunosuppressive Microenvironment ◽  
Immune Exclusion

Despite a few cases of long-responder patients, immunotherapy with anti-PD-(L)1 has so far proved rather disappointing in monotherapy in metastatic breast cancer, prompting the use of synergistic therapeutic combinations incorporating immunotherapy by immune-checkpoint inhibitors. In addition, a better understanding of both the mechanisms of sensitivity and resistance to immunotherapy, as well as the immunological effects of the usual treatments for breast cancer, make it possible to rationally consider this type of therapeutic combination. For several years, certain treatments, commonly used to treat patients with breast cancer, have shown that in addition to their direct cytotoxic effects, they may have an impact on the tumor immune microenvironment, by increasing the antigenicity and/or immunogenicity of a “cold” tumor, targeting the immunosuppressive microenvironment or counteracting the immune-exclusion profile. This review focuses on preclinical immunologic synergic mechanisms of various standard therapeutic approaches with anti-PD-(L)1, and discusses the potential clinical use of anti-PD-1/L1 combinations in metastatic or early breast cancer.

scholarly journals Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yasser Tabana ◽  
Isobel S. Okoye ◽  
Arno Siraki ◽  
Shokrollah Elahi ◽  
Khaled H. Barakat
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Checkpoint Inhibitors ◽  
Clinical Results ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Microenvironment ◽  
Problem Drug ◽  
Treat Breast Cancer

The burden of breast cancer is imposing a huge global problem. Drug discovery research and novel approaches to treat breast cancer have been carried out extensively over the last decades. Although immune checkpoint inhibitors are showing promising preclinical and clinical results in treating breast cancer, they are facing multiple limitations. From an immunological perspective, a recent report highlighted breast cancer as an “inflamed tumor” with an immunosuppressive microenvironment. Consequently, researchers have been focusing on identifying novel immunological targets that can tune up the tumor immune microenvironment. In this context, several novel non-classical immune targets have been targeted to determine their ability to uncouple immunoregulatory pathways at play in the tumor microenvironment. This article will highlight strategies designed to increase the immunogenicity of the breast tumor microenvironment. It also addresses the latest studies on targets which can enhance immune responses to breast cancer and discusses examples of preclinical and clinical trial landscapes that utilize these targets.

Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1034-1034
Author(s):  
Justin Wayne Wong Tiu-lim ◽  
Jun Yin ◽  
Joanne Xiu ◽  
Wolfgang Michael Korn ◽  
Heinz-Josef Lenz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Metastatic Breast ◽  
Molecular Alterations ◽  
Ras Genes ◽  
Mutational Status ◽  
Pathway Activation ◽  
Class 1

1034 Background: The Ras-MAPK pathway is a known driver of tumorigenesis and therapeutic target in a variety of cancers. Alterations in this pathway have been linked to decreased tumor immunogenicity. However, molecular alterations in the Ras-MAPK are rare in breast cancer (BC) and their clinical implications remain unclear. As mutational status does not accurately correlate with transcriptional activity, a MAPK pathway activity score (MPAS, Wagle et al., 2018, npj Precision Medicine) is indicative of MAPK activation and correlates with response to MEK (MEKi) or BRAF inhibition (BRAFi). Our goal was to determine the frequency of molecular alterations in the Ras-MAPK and correlate to MAPK pathway activation in MBC. Methods: A total of 6464 BC samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS and immune cell fraction (ICF, Quantiseq) were assessed by mRNA analysis. Wilcoxon, Fisher’s exact, or Dunnett’s test was used. All results shown were statistically significant (p < 0.05). Results: The predominant alteration of RAS genes was mutation followed by amplification, no fusions were detected (Table). Only 0.17% of all tumors harbor KRAS G12c mutations. The highest MPAS scores were found in KRAS mutants (mut), HRAS mut (Q61, G1213), BRAF V600 (class 1) mut and NRAS Q61 mut (Table) and therefore used to define Genomic MAPK Activated Tumors (GMAT). GMAT compared to wild type (WT) had significantly higher PD-L1 expression, TMB and MSI/dMMR. GMAT had less B cells (3.4% vs 4.4%), more M1 Macrophages (4.4% vs 3.4%) and neutrophils (5.5% vs 2.7%) regardless of HR status but less NK cells (2.3% s 3.0%), MSDCs (0.9% vs 3.0%) only in HR- tumors with respect to WT. GMAT tumors showed more frequent mutation rate (mr) of PIK3CA (HR+: 57.3% vs 40%; HR-: 41.9% vs 17.9%). HR+ tumors had a higher mr of MSH3 (11.8% vs 0.6%) while HR- tumors had higher mr of PIK3R1 (9.6% vs 3.8%), RhoA (5.3% vs 0.5%), DNA repair genes (TERT, 18.2% vs 1.0%; ARID1A, 18.2% vs 5.9%; PRKDC, 3.9% vs 0) and lower TP53 mr (54.5% vs 85.8%) compared to WT. Conclusions: Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi. GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.[Table: see text]

Abstract 1786: Targeting the immunosuppressive microenvironment of metastatic breast cancer with viroimmunotherapy

2021 ◽  
Author(s):  
Sagar Shashikant Sohoni ◽  
Teresa Nguyen ◽  
Dong Ho Shin ◽  
Xuejun Fan ◽  
Jiang Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Immunosuppressive Microenvironment

scholarly journals Targeted Therapies in Triple-Negative Breast Cancer

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 159-166 ◽  
Author(s):  
Frederik Marmé ◽  
Andreas Schneeweiss
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Chemotherapy Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Receptor Subtype

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed.

scholarly journals Breast Cancer Immunotherapy: From Biology to Current Clinical Applications

2020 ◽  
pp. 113-124
Author(s):  
Jorge Henrique Santos Leal ◽  
Heather McArthur
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Immune Checkpoint ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii

Therapeutic strategies for the treatment of breast cancer have historically been determined by the presence or absence of hormone receptors and HER2 amplification and/or protein expression. For patients with breast cancer that lack these biomarkers, the so-called ‘triple-negative’ subtype, chemotherapy has been the cornerstone of cure and palliation. However, with the recent successful development of immune checkpoint molecules that target cytotoxic T-lymphocyte antigen-4, programmed cell death-1 (PD-1), and PD-ligand 1 (PD-L1), improved survival has been reported across a range of tumour types including melanoma, lung, and bladder cancer. In metastatic breast cancer, trials of single-agent immune checkpoint inhibitors (ICI) have resulted in limited overall response rates; however, strategies that combine local or systemic therapies with ICI have improved response rates and, in some cases, improved survival. For example, the addition of an anti-PD-L1 inhibitor, atezolizumab, to nab-paclitaxel chemotherapy for newly diagnosed metastatic triple-negative breast cancer demonstrated an improvement in overall survival in an informal analysis of the PD-L1-positive subset in a recently reported Phase III clinical trial. These results ultimately led to U.S. Food and Drug Administration (FDA) approval for an ICI for the treatment of breast cancer, with numerous other health authorities following suit. Herein, the authors describe the biology behind ICI, the rationale for ICI administration in breast cancer, the related clinical trial data reported to date, and promising future strategies.

scholarly journals Successful Treatment of Mycobacterium chelonae Keratitis Within a Corneal Transplant Using Intrastromal Amikacin Injections—A Case Report Demonstrating the Fundamental Principles and Challenges of Infective Keratitis Management and Novel Therapeutic Approaches

2019 ◽  
Vol 6 (8) ◽  
Author(s):  
Nancy Louisa Merridew ◽  
Ravinder Singh Phagura ◽  
Edward Anderson ◽  
Louise Anne Cooley ◽  
Graeme Alfred Pollock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Case Report ◽  
Transplant Recipient ◽  
Effective Treatment ◽  
Metastatic Breast ◽  
Corneal Transplant ◽  
Therapeutic Approaches ◽  
Mycobacterium Chelonae ◽  
Novel Therapeutic

Abstract Mycobacterium chelonae keratitis is rare and difficult to treat. This is the first known case worldwide of effective treatment using intrastromal amikacin injections in a corneal transplant recipient who had metastatic breast cancer. The challenges and principles of management, applicable to other causes of infective keratitis, are reviewed.

Circulating PD-L1 (programmed death-ligand 1) and outcomes in a HER2-positive metastatic breast cancer cohort treated with first-line trastuzumab.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1024-1024 ◽  
Author(s):  
Ayesha Ali ◽  
Laura Krecko ◽  
Kim Leitzel ◽  
Suhail M. Ali ◽  
Joseph J. Drabick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
First Line ◽  
Her2 Positive ◽  
Breast Cancer Cohort

1024 Background: Recently the immune checkpoint inhibitors (ICIs) have demonstrated efficacy across a wide variety of cancers, but have been less effective in breast cancer. PD-L1 (B7-H1, CD274) is a ligand produced by many tumor cells and some immune cells, and suppresses the T cell immune response. This allows tumor cells to escape immune detection. PD-L1 is used as a companion tumor tissue IHC biomarker for patient selection for some of the FDA-approved ICIs (pembrolizumab), but not for others (nivolumab, atezolizumab). Circulating PD-L1 has been detected in multiple myeloma, renal, lung, and gastric cancer, but not in breast cancer. Here we correlated serum PD-L1 levels with outcome in a HER2-positive metastatic breast cancer cohort treated with trastuzumab. Methods: Pretreatment serum was obtained from 63 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. A novel ELLA microfluidic channel immunoassay platform (ProteinSimple, San Jose, CA) was employed to quantitate serum PD-L1. Serum PD-L1 levels were analyzed using continuous, quartile, and dichotomous (25%, median, and 75%) cutpoints. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: On a continuous basis, patients with higher serum PD-L1 had a significantly reduced PFS (p = 0.045) and overall survival OS (p = 0.004) compared to patients with lower serum PD-L1 levels. Patients with the higher quartiles of serum PD-L1 also trended to have reduced PFS (0.11) and significantly reduced OS (p = 0.015) compared to the lower quartiles of serum PD-L1. Finally, using either the 25th or 75th percentile of serum PD-L1 as dichotomous cutpoint, patients with higher serum PD-L1 had significantly reduced OS (p = 0.04). Conclusions: Higher circulating PD-L1 levels were prognostic for reduced PFS and OS in HER2-positive metastatic breast cancer patients treated with first-line trastuzumab. Circulating PD-L1 deserves further study for prognostic and predictive biomarker utility in larger trials of immune checkpoint inhibitors and other immunotherapies in breast and other cancers. AA, LK contributed equally.

Comparison of the uptake of untargeted and targeted immunostimulatory nanoparticles by immune cells in the microenvironment of metastatic breast cancer

2021 ◽  
Author(s):  
Gil Covarrubias ◽  
Taylor J. Moon ◽  
Georgia Loutrianakis ◽  
Haley M. Sims ◽  
Mayura P. Umapathy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Immune Cells ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Late Metastasis

Using common targeting ligands, we developed four nanoparticle variants and assessed their microdistribution in the tumor immune microenvironment in three different breast cancer landscapes, including primary tumor, early and late metastasis. 

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