Immune microenvironment profiling of breast cancer brain metastases using multiplex immunofluorescence.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2526-2526
Author(s):  
Gaia Griguolo ◽  
Anna Tosi ◽  
Valentina Guarneri ◽  
Maria Vittoria Dieci ◽  
Susan Fineberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Spatial Information ◽  
Immune Cell ◽  
Total Sample ◽  
Clinical Variable ◽  
Immune Microenvironment ◽  
Significant Difference ◽  
Tumor Recognition ◽  
Breast Cancer Brain Metastases

2526 Background: Despite clinical implications, the complexity of brain metastases (BM) immune microenvironment in breast cancer (BC) patients is poorly understood. Multiplex immunofluorescence (mIF), a novel imaging technique allowing simultaneous visualization and quantification of several IF labeled proteins while maintaining spatial information, holds promise to comprehensively describe BCBM immune microenvironment, potentially providing valuable information to improve treatment. Methods: Clinical data and archival BM samples were collected for 60 BC patients undergoing neurosurgery (2003-2018) at three institutions. BM immune contexture was characterized using a custom mIF panel, including cell subtyping (CD4, CD8, FOXP3, CD68), activation (Granzyme B) and localization (keratin for tumor recognition) markers. Mean immune cell density (cells/mm2) for each sample was determined by digital image analysis and classified in tumor and stroma areas. Associations between immune subpopulations, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Up to date, 30 BCBM samples have been analyzed; 33% HR+/HER2-, 20% HR-/HER2+, 10% HR+/HER2+, 37% HR-/HER2-. At a median follow-up of 46 months, BC subtype was the only clinical variable associated with OS (longest for HER2+ and shortest for HR-/HER2-, log-rank p = 0.002). In the total sample area, no significant difference in immune cell densities was observed according to BC subtype. In the tumor area, HR+/HER2- tumors showed higher densities of CD8+ and CD68+ cells compared to other subtypes (p = 0.036 and p = 0.016, respectively). In stroma, HR-/HER2- tumors presented numerically higher densities of CD4+ and FOXP3+ cells and higher ratio of CD4/CD8 and FOXP3/CD8 ratio (not statistically significant). Higher CD4/CD8 and FOXP3/CD8 ratio in the stroma was significantly associated with worse OS, even after correction by BC subtype (Table). Conclusions: In BCBM, immune infiltrate differs according to BC subtype. Preliminary results suggest that a more tolerogenic immune microenvironment is associated with worse OS and might represent a target for optimization of immunotherapy for these patients. Updated results for all 60 patients will be presented. [Table: see text]

Genomic profiling of breast cancer brain metastases reveals targetable alterations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2525-2525
Author(s):  
Sheheryar Kairas Kabraji ◽  
Liam F. Spurr ◽  
Melissa E Hughes ◽  
Yvonne Y. Li ◽  
Jose Pablo Leone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Copy Number ◽  
Enrichment Analysis ◽  
Fisher Exact Test ◽  
Copy Number Alterations ◽  
Genomic Alterations ◽  
Primary Tumors ◽  
Significant Difference ◽  
Breast Cancer Brain Metastases

2525 Background: Genomic characterization of breast cancer brain metastases (BCBMs) has thus far been limited. The objective of this study was to describe the landscape of genomic alterations in patients (pts) with BCBMs. Methods: Targeted next-generation DNA sequencing of > 300 cancer-related genes (OncoPanel) was prospectively performed on primary and metastatic (met) tumors in 321 pts with a diagnosis of BCBM between August 2016 and April 2019 at Dana-Farber Cancer Institute (table). Enrichment analysis of genomic alterations was performed using a two-sided Fisher exact test and differences in tumor mutation burden (TMB) between groups were assessed using two-sided Mann-Whitney U test. Multiple comparison correction was performed using the Benjamini-Hochberg procedure. Results: All subtypes were represented in BCBM (25 HR+/HER2-; 24 HR+/HER2+; 27 HR-/HER2+; 18 TNBC; 5 unknown; n = 99) and extracranial (EC) samples: (96 HR+/HER2-; 32 HR+/HER2+; 22 HR-/HER2+; 41 TNBC; 31 unknown; n = 222). BCBMs were found most commonly to have mutations or copy number alterations in TP53, ERBB2, PIK3CA, GATA3, PTEN, ESR1, CDH1, BRCA2, ARID1A, BRCA1 (>5% frequency, table). Two pts acquired ERBB2 amplification (amp) between the matched primary breast sample and brain met. In pair-wise comparisons of BCBMs to unmatched primaries or EC mets, only ERBB2 amp was significantly enriched (table, † = adjusted p < 0.05). There was no significant difference in TMB between BCBM and EC mets (median 9.12 vs 7.26, p = 0.15). In contrast, TMB was significantly higher in BCBMs compared to unmatched primaries (median 9.12 vs 7.26, p=0.005). Conclusions: BCBMs display similar mutations and copy number alterations compared to primary tumors and EC mets in pts with BCBM. These data suggest that BCBMs contain actionable genomic alterations that are most often also reflected in EC disease. Alterations in ERBB2, PIK3CA/PTEN, and BRCA1/2 represent potentially targetable alterations in pts with BCBM. [Table: see text]

Profiling of immune checkpoint biomarkers by multiplex immunofluorescence in breast cancer brain metastases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2021-2021
Author(s):  
Gaia Griguolo ◽  
Anna Tosi ◽  
Valentina Guarneri ◽  
Maria Vittoria Dieci ◽  
Susan Fineberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Cell Density ◽  
Immune Checkpoint ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Marker Density ◽  
Immune Microenvironment ◽  
Significant Difference ◽  
M2 Macrophage Polarization

2021 Background: Despite potential clinical implications, the complexity of immune microenvironment in breast cancer (BC) brain metastases (BM) is still poorly understood. Multiplex immunofluorescence (mIF) allows simultaneous visualization of several IF labeled proteins while maintaining spatial information. This novel technique can be used to comprehensively describe BCBM immune microenvironment, potentially providing useful information to guide novel therapeutic approaches. Methods: Clinical data and archival BM samples from 60 BC patients undergoing neurosurgery (2003-2018) at three institutions were collected. BCBMs were characterized using a custom mIF panel, including immune checkpoint and co-inhibitory molecules (CD3, PD1, PD-L1, TIM3, LAG3, CD163) and localization (keratin for tumor recognition) markers. Mean marker density was determined by digital image analysis (positive cells/mm2) and classified in tumor and stroma areas. Associations between immune marker densities, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Sixty BCBM samples were analyzed; 32% HR+/HER2-, 38% HER2+, 30% HR-/HER2-. At a median follow-up of 43 months, the only clinical variable associated with OS was BC subtype (shortest for HR-/HER2- and longest for HER2+, p=0.02). In the total sample area and tumor area, no significant difference in marker density was observed according to BC subtype. In the stroma area, a significant difference in TIM3+ cell density was observed according to BC subtype (highest density in HR+/HER2- and lowest density in HER2+ tumors, Kruskal-Wallis p=0.017). Higher CD163 density (a marker of M2 macrophage polarization), both in the tumor and in the stroma area, was significantly associated with worse OS, even after correction by BC subtype. In the subgroup of patients with HR+/HER2- BCBM, high TIM3+ cell density in the stroma area was significantly associated with longer OS (median OS 54.1 versus 23 months respectively for TIM3+ density above and below median value; p=0.01). Conclusions: In BCBM, stromal TIM3+ immune infiltrate differs according to BC subtype. M2 macrophage polarization is consistently associated with worse OS across all BC subtypes and might represent a potential therapeutic target for these patients.[Table: see text]

Characteristics of patients with prolonged survival after breast cancer brain metastases (BCBM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20659-e20659
Author(s):  
Zorica Tomasevic ◽  
Zeljko Kovac ◽  
Zoran Tomasevic
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Gamma Knife ◽  
Prolonged Survival ◽  
Preventive Strategies ◽  
Short Survival ◽  
Significant Difference ◽  
Group A ◽  
Breast Cancer Brain Metastases ◽  
Extended Survival

e20659 Background: BCBM development predicts short survival for majority of pts. However, 10%, of pts survive up to 2 yrs, and some of those pts has extended survival to more than 2 yrs after BM. Whether there are differences between pts in those arbitrary determined subgroups with prolonged survival is still unknown. The aim of this paper is to analyze and compare characteristics of BCBM pts with survival after BM (BMs) between ≥ 12 - 24 months and ≥ 25 month. Methods: A 193 consecutive BCBM pts have been registered during 5 yrs (January 2008-December 2012). All BM were confirmed by CT/MRI. All pts underwent BM treatment: WBRT 160 (83%); postoperative WBRT in 32 pts (17 %); gamma knife in 7 pts (3,6 %). BMs is known for 169 pts and was median 5,5 months (range 1-72+ months). Only pts with BMs ≥ 12 months were considered for this analysis. Results: 39/169 pts (23%) with median BMs 19 months (range 12-72+) were identified and divided in 2 groups (see Table). MBC in other organ sites, predominantly non visceral, was present in 45% pts (A) and in 40% (B), at the time of BM diagnose. There was no statistically significant difference between group A and B. Conclusions: Despite BM, a subgroup of pts still has indolent MBC course with median BMs of 19 months, and 6% has BMs of median 35 months. There were no statistically significant difference between standard clinical/pathological parameters Therefore, other characteristics, both patients and BC/BM must be considered. Better understanding of crucial characteristics of this subgroup of BCBM pts, is needed because these pts might potentially represents the best candidates for future BM preventive strategies. [Table: see text]

scholarly journals VWCE as a potential biomarker associated with immune infiltrates in breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qin Huo ◽  
Zhenwei Li ◽  
Siqi Chen ◽  
Juan Wang ◽  
Jiaying Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Her2 Status ◽  
Cancer Tissue ◽  
M2 Macrophage ◽  
Breast Cancer Patients ◽  
Immune Infiltration ◽  
Potential Biomarker ◽  
Significant Difference ◽  
Factor C

Abstract Purpose Von Willebrand Factor C and EGF Domains (VWCE) is an important gene that regulates cell adhesion, migration, and interaction. However, the correlation between VWCE expression and immune infiltrating in breast cancer remain unclear. In this study, we investigated the correlation between VWCE expression and immune infiltration levels in breast cancer. Methods The expression of VWCE was analyzed by the tumor immune estimation resource (TIMER) and DriverDB databases. Furthermore, genes co-expressed with VWCE and gene ontology (GO) enrichment analysis were investigated by the STRING and Enrichr web servers. Also, we performed the single nucleotide variation (SNV), copy number variation (CNV), and pathway activity analysis through GSCALite. Subsequently, the relationship between VWCE expression and tumor immunity was analyzed by TIMER and TISIDB databases, and further verified the results using Quantitative Real-Time PCR (RT-PCR), Western blotting, and immunohistochemistry. Results The results showed that the expression of VWCE mRNA in breast cancer tissue was significantly lower than that in normal tissues. We found that the expression level of VWCE was associated with subtypes, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status of breast cancer patients, but there was no significant difference in the expression of VWCE was found in age and nodal status. Further analyses indicated that VWCE was correlated with the activation or inhibition of multiple oncogenic pathways. Additionally, VWCE expression was negatively correlated with the expression of STAT1 (Th1 marker, r = − 0.12, p = 6e−05), but positively correlated with the expression of MS4A4A (r = 0.28, p = 0). These results suggested that the expression of VWCE was correlated with immune infiltration levels of Th1 and M2 macrophage in breast cancer. Conclusions In our study, VWCE expression was associated with a better prognosis and was immune infiltration in breast cancer. These findings demonstrate that VWCE is a potential prognostic biomarker and correlated with tumor immune cell infiltration, and maybe a promising therapeutic target in breast cancer.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases

2019 ◽  
Vol 144 (3) ◽  
pp. 583-589 ◽  
Author(s):  
Nicholas B. Figura ◽  
Thrisha K. Potluri ◽  
Homan Mohammadi ◽  
Daniel E. Oliver ◽  
John A. Arrington ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Hormone Receptor ◽  
Stereotactic Radiation ◽  
Hormone Receptor Positive ◽  
Breast Cancer Brain Metastases ◽  
Positive Breast Cancer

Breast cancer brain metastases: Molecular subtype, treatment and survival

2016 ◽  
Vol 36 (4) ◽  
pp. 133-141 ◽  
Author(s):  
Jennifer A. Crozier ◽  
Lauren F. Cornell ◽  
Bhupendra Rawal ◽  
Edith A. Perez
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Molecular Subtype ◽  
Breast Cancer Brain Metastases

scholarly journals MicroRNAs and Extracellular Vesicles as Distinctive Biomarkers of Precocious and Advanced Stages of Breast Cancer Brain Metastases Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5214
Author(s):  
Inês Figueira ◽  
Joana Godinho-Pereira ◽  
Sofia Galego ◽  
Joana Maia ◽  
János Haskó ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Brain Metastases ◽  
Extracellular Vesicles ◽  
Triple Negative ◽  
Survival Rates ◽  
Brain Parenchyma ◽  
Advanced Stages ◽  
Breast Cancer Brain Metastases

Triple negative breast cancer presents higher mortality and poorer survival rates than other breast cancer (BC) types, due to the proneness to brain metastases formation, which are usually diagnosed at advanced stages. Therefore, the discovery of BC brain metastases (BCBM) biomarkers appears pivotal for a timely intervention. With this work, we aimed to disclose microRNAs (miRNAs) and extracellular vesicles (EVs) in the circulation as biomarkers of BCBM formation. Using a BCBM animal model, we analyzed EVs in plasma by nanoparticle tracking analysis and ascertained their blood-brain barrier (BBB) origin by flow cytometry. We further evaluated circulating miRNAs by RT-qPCR and their brain expression by in situ hybridization. In parallel, a cellular model of BCBM formation, combining triple negative BC cells and BBB endothelial cells, was used to differentiate the origin of biomarkers. Established metastases were associated with an increased content of circulating EVs, particularly of BBB origin. Interestingly, deregulated miRNAs in the circulation were observed prior to BCBM detection, and their brain origin was suggested by matching alterations in brain parenchyma. In vitro studies indicated that miR-194-5p and miR-205-5p are expressed and released by BC cells, endothelial cells and during their interaction. These results highlight miRNAs and EVs as biomarkers of BCBM in early and advanced stages, respectively.

Current Treatment Strategies in Breast Cancer Brain Metastases

2019 ◽  
pp. 267-279
Author(s):  
Rupert Bartsch ◽  
Elisabeth Sophie Bergen ◽  
Karin Dieckmann ◽  
Anna Sophie Berghoff ◽  
Matthias Preusser
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Breast Cancer Brain Metastases
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