scholarly journals Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5225
Author(s):  
Seri Jeong ◽  
Nuri Lee ◽  
Min-Jeong Park ◽  
Kibum Jeon ◽  
Wonkeun Song
Keyword(s):  
Breast Cancer ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Enzyme Linked Immunosorbent Assay ◽  
Scoring Methods ◽  
Comprehensive Understanding ◽  
Tissue Samples ◽  
Programmed Death ◽  
Poor Outcomes

Approximately 20% of breast cancer (BC) patients suffer from distant metastasis. The incidence and prevalence rates of metastatic BC have increased annually. Immune checkpoint inhibitors are an emerging area of treatment, especially for metastatic patients with poor outcomes. Several antibody drugs have been developed and approved for companion testing of the programmed death protine-1 (PD-1) axis. We reviewed currently used laboratory methodologies for assays determining PD-1 axis to provide a comprehensive understanding of principles, advantages, and drawbacks involved in their implementation. The most commonly used method is immunohistochemistry (92.9%) for PD-L1 expression using tissue samples (96.4%). The commonly used anti-PD-L1 antibody clone were commercially available 22C3 (30.8%), SP142 (19.2%), SP263 (15.4%), and E1L3N (11.5%). Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay that target soluble PD-ligand (L)1 were developed and popularized in 2019–2021, in contrast to 2016–2018. Easy accessibility and non-invasiveness due to the use of blood samples, quantitative outputs, and relatively rapid turnaround times make them more preferable. Regarding scoring methods, a combination of tumor and immune cells (45.5% in 2016–2018 to 57.1% in 2019–2021) rather than each cell alone became more popular. Information about antibody clones, platforms, scoring methods, and related companion drugs is recommended for reporting PD-L1 expression.

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.

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]

scholarly journals The Change of Soluble Programmed Cell Death-Ligand 1 (sPD-L1) in Glioma Patients Receiving Radiotherapy and Its Impact on Clinical Outcome

2020 ◽  
Author(s):  
Xing-chen Ding ◽  
Liang-liang Wang ◽  
Yu-fang Zhu ◽  
Jia Yang ◽  
Jin-ming Yu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Enzyme Linked Immunosorbent Assay ◽  
Murine Models ◽  
Isocitrate Dehydrogenase 1 ◽  
Ki 67 ◽  
Kaplan Meier ◽  
Programmed Death ◽  
Potential Biomarker ◽  
Before And After

Abstract Background: It has been proved that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in extracranial malignancies. However, the expression of sPD-L1 in glioma patients receiving radiotherapy (RT) still remains unclear.The purpose of this study is to evaluate the concentration of sPD-L1in the plasma of glioma patients before and after RT, and to explore its relationship with clinical outcomes.Methods: Between October 2017 and September 2018, the glioma patients treated with RT (30 ± 10 Gy, 2 Gy/f) were enrolled and the blood samples were collected before and after RT. We quantified the sPD-L1 levels by enzyme-linked immunosorbent assay (ELISA). The isocitrate dehydrogenase-1 (IDH-1) promoter status and Ki-67 expression were evaluated by immunohistochemistry. The murine models of glioma were used to address whether circulating sPD-L1 molecules are directly targeted by the anti-PD-L1 antibody. The associations between sPD-L1 and clinical features were assessed with Pearson or Spearman correlation. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method.Results: Sixty glioma patients were included, with the median age 52-year-old. The proportion of grade I, II, III, IV were 6.7%, 23.3%, 28.4% and 41.6%, respectively. The baseline sPD-L1 levels were significantly associated with tumor grades, IDH-1 mutation status and Ki-67 expression. Using 14.35 pg/mL as the cutoff, significantly worse PFS and OS were both observed in patients with higher baseline level of sPD-L1 (P = 0.027, 0.008, respectively). RT significantly increased the mean level of sPD-L1 (P < 0.001). Further analysis showed that increased level of sPD-L1 in IDH-1 mutation patients was higher than that in wide-type ones. Furthermore, the murine models of glioma indicate that sPD-L1 can be blocked by anti-PD-L1 antibody. Conclusion: This study reported that sPD-L1 might be a potential biomarker to predict the outcome in glioma receiving RT. The elevated level of sPD-L1 after RT suggested that the strategy of combination with immune checkpoint inhibitors and RT might be promising for glioma, especially for patients with IDH-1 mutation.

scholarly journals Two may be better than one: PD-1/PD-L1 blockade combination approaches in metastatic breast cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
David B. Page ◽  
Harry Bear ◽  
Sangeetha Prabhakaran ◽  
Margaret E. Gatti-Mays ◽  
Alexandra Thomas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Practice ◽  
Clinical Data ◽  
Targeted Therapies ◽  
Metastatic Breast ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Better Than ◽  
Systemic Therapies

Abstract Antibodies blocking programmed death 1 (anti-PD-1) or its ligand (anti-PD-L1) are associated with modest response rates as monotherapy in metastatic breast cancer, but are generally well tolerated and capable of generating dramatic and durable benefit in a minority of patients. Anti-PD-1/L1 antibodies are also safe when administered in combination with a variety of systemic therapies (chemotherapy, targeted therapies), as well as with radiotherapy. We summarize preclinical, translational, and preliminary clinical data in support of combination approaches with anti-PD-1/L1 in metastatic breast cancer, focusing on potential mechanisms of synergy, and considerations for clinical practice and future investigation.

scholarly journals Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 809 ◽  
Author(s):  
Kloten ◽  
Lampignano ◽  
Krahn ◽  
Schlange
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Tissue Samples ◽  
Programmed Death ◽  
Nsclc Patients

Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.

scholarly journals Blockade of PD-1, PD-L1, and TIM-3 Altered Distinct Immune- and Cancer-Related Signaling Pathways in the Transcriptome of Human Breast Cancer Explants

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 703
Author(s):  
Reem Saleh ◽  
Salman M. Toor ◽  
Dana Al-Ali ◽  
Varun Sasidharan Nair ◽  
Eyad Elkord
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Checkpoint Inhibitors ◽  
Rna Seq ◽  
Human Breast ◽  
Compensatory Mechanisms ◽  
Transcriptomic Data ◽  
Functional Studies ◽  
Programmed Death ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) are yet to have a major advantage over conventional therapies, as only a fraction of patients benefit from the currently approved ICIs and their response rates remain low. We investigated the effects of different ICIs—anti-programmed cell death protein 1 (PD-1), anti-programmed death ligand-1 (PD-L1), and anti-T cell immunoglobulin and mucin-domain containing-3 (TIM-3)—on human primary breast cancer explant cultures using RNA-Seq. Transcriptomic data revealed that PD-1, PD-L1, and TIM-3 blockade follow unique mechanisms by upregulating or downregulating distinct pathways, but they collectively enhance immune responses and suppress cancer-related pathways to exert anti-tumorigenic effects. We also found that these ICIs upregulated the expression of other IC genes, suggesting that blocking one IC can upregulate alternative ICs, potentially giving rise to compensatory mechanisms by which tumor cells evade anti-tumor immunity. Overall, the transcriptomic data revealed some unique mechanisms of the action of monoclonal antibodies (mAbs) targeting PD-1, PD-L1, and TIM-3 in human breast cancer explants. However, further investigations and functional studies are warranted to validate these findings.

scholarly journals Baseline Lymphopenia: A Predictor Of Poor Outcomes In HER2 positive Metastatic Breast Cancer Treated With Trastuzumab

2019 ◽  
Vol Volume 13 ◽  
pp. 3727-3734
Author(s):  
Yi-Qun Che ◽  
Yue Zhang ◽  
Di Wang ◽  
Hui-Ying Liu ◽  
Di Shen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Poor Outcomes

scholarly journals Impact of systemic therapy on circulating leukocyte populations in patients with metastatic breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna-Maria Larsson ◽  
Anna Roxå ◽  
Karin Leandersson ◽  
Caroline Bergenfelz
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Natural Killer ◽  
Endocrine Therapy ◽  
Immune Cells ◽  
Systemic Therapy ◽  
Immune Cell ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Cell Populations

Abstract Tumors affect the immune system, locally and systemically. The frequencies of specific circulating immune cell populations correlate with disease progression as well as prognosis of the patients. Although largely neglected, conventional antitumoral therapies often possess immunomodulatory properties and affect the levels of specific immune cell populations. Most information, however, derive from animal or in vitro studies. As this could impact prognosis as well as response to therapy, further studies of the effects of treatment on circulating immune cells in patients are warranted. In this pilot study, we evaluated a wide panel of circulating immune cells over time (up to six months) in ten patients with metastatic breast cancer receiving standard antitumoral regimens. Overall, endocrine therapy tends to enrich for natural killer (NK) and natural killer T (NKT) cells in the circulation, whereas both chemotherapy and endocrine therapy reduce the levels of circulating monocytic myeloid-derived suppressor cells (Mo-MDSCs). This indicates that the systemic immunosuppressive profile observed in patients tends to revert over the course of systemic therapy and holds promise for future combination treatment with standard antitumoral agents and immunotherapy.

Neuregulin (NRG) expression modulates clinical response to trastuzumab in patients with metastatic breast cancer (MBC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10069-10069
Author(s):  
E. De Alava ◽  
M. Abad ◽  
C. A. Rodriguez ◽  
J. C. Montero ◽  
E. Serrano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast ◽  
Response To Treatment ◽  
Tissue Samples ◽  
Cytoplasmic Staining ◽  
Frozen Tissue ◽  
The Relationship ◽  
Erbb2 Amplification ◽  
Erbb2 Overexpression

10069 Background: ErbB2 overexpression is the major determinant of response to trastuzumab (Herceptin, H). Recently, some authors have reported the potential role of the expression of NRG on ErbB2 activation in breast cancer cells, and its consequences in response to treatment with H. In the present study we analyze the relationship between response to H and expression of ErbB2 and NRG in patients (pt) with MBC. Methods: Data and frozen tissue samples from 30 consecutive pt with MBC and positive ErbB2 at diagnosis [Immunohistochemistry (IHC)] were collected. All pt were treated with an Herceptin-based regimen. Central Pathologic review of ErbB2 expression was performed in all samples (Herceptest and FISH). NRG expression was studied by IHC on paraffin embedded material and by Western blotting on frozen tissue using an antibody raised against the intracellular domain of NRG. NRG expression by IHC was evaluated using a semiquantitative scoring system that assesses both extension and intensity of cytoplasmic staining. Correlation between ErbB2 and NRG expression and its influence in response to H was analyzed. Characteristics of pt: Median Age: 54; Median mts sites: 2; Treatment: H alone:1 pt; H+Taxol:15 pt; H+Taxol+Carbo: 4 pt; H+Taxol+Lip.Doxorub:2 pt, H+Vinorelbine:7 pt; H+CDDP:1 pt. Results: ORR: 76% (CR:23%, PR:53%). Median TTP: 7.8 m. After central Pathologic review, a total of 20 tumors showed ErbB2 amplification by FISH and 19 of them were Herceptest 3+. A positive correlation was observed between ErbB2 amplification and NRG expression. All complete responses (n=7) were seen in pt with ErbB2 amplification. Interestingly, in the group of tumors without ErbB2 amplification (n=10), 7 had high NRG expression levels, as assessed by IHC. Six out of these 7 tumors having high levels of NRG expression, exhibited partial responses. NRG expression, in turn, did not have impact on response among ErbB2 amplified tumors. Conclusions: These preliminary results suggest that responses to H regimens in pt with MBC can be seen in pt lacking ErbB2 amplification in presence of high levels of expression of transmembrane ligand NRG. This suggests that the group of pt that may benefit from treatment with H could be broader than currently established. A confirmatory study is ongoing in a larger series. No significant financial relationships to disclose.

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