Abstract 4641: Improved chemotherapeutic delivery to brain metastases with targeted nanoparticles in preclinical breast cancer brain metastasis models

2018 ◽  
Author(s):  
Emily A. Wyatt ◽  
Mark E. Davis
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Targeted Nanoparticles ◽  
Breast Cancer Brain Metastasis ◽  
Metastasis Models ◽  
Chemotherapeutic Delivery

scholarly journals BSCI-25. THE ROLE OF THE IFNγ PATHWAY IN BREAST CANCER BRAIN METASTASIS FORMATION

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i5-i5
Author(s):  
Route Pedrosa ◽  
Benjamin Schrijver ◽  
Rute B Marques ◽  
Pieter J M Leenen ◽  
Wim A Dik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
T Cell Response ◽  
Activated T Cells ◽  
Breast Cancer Brain Metastasis

Abstract In previous work, we showed the prominence of the T cell response in the formation of brain metastases of primary ER-negative breast cancers. We also showed that prior co-cultured breast cancer cells with stimulated T lymphocytes bear an overexpression of Guanylate-binding protein 1 (GBP1) and possess an increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to the brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. In the present work, we show that activated CD8+ cytotoxic T lymphocytes, rather than CD4+ lymphocytes, are the main cause of increasing the ability of breast cancer cells to cross the BBB. While synthetic IFNγ does not change the ability of breast cancer cells to cross the BBB, this study shows that the T lymphocyte-secreted IFNγ activates the STAT1-dependent IFNγ pathway in breast cancer cells, enabling them to cross the in vitro BBB. Direct inhibition of soluble IFNγ or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. The results illustrate that IFNγ signaling pathway is one of the crucial pathways in the formation of brain metastasis of ER- breast cancer. The interference with the IFNγ pathway will develop preventive strategies against the formation of brain metastases of breast cancer.

Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2049-2049 ◽  
Author(s):  
Jessie Narloch ◽  
Catherine Luedke ◽  
Gloria Broadwater ◽  
Nolan Priedigkeit ◽  
Allison Hall ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Infiltrating Lymphocytes ◽  
Cox Proportional Hazards Model ◽  
Her2 Status ◽  
Primary Tumors ◽  
Metastatic Setting ◽  
Breast Cancer Brain Metastasis ◽  
Infiltrating Lymphocytes

2049 Background: Breast cancer brain metastasis (BCBM) is frequent in advanced disease, has limited therapies, and is associated with poor prognosis. Increased stromal tumor infiltrating lymphocytes (sTILs) are prognostic in triple-negative breast cancer (TNBC) and predictive of therapeutic response in early breast cancer (BC). However, little is known about sTILs in the metastatic setting. We compared %sTILs between the largest known cohort of matched primary tumors and BCBM and correlated the results with clinical endpoints. Methods: We retrospectively investigated 37 matched primary tumors and BCBM tissue from three institutions. In addition, we identified 29 primary tumors from patients later diagnosed with BCBM. H&E-stained sections were manually measured for %sTILs using standard criteria. Wilcoxon signed rank tests assessed for changes in %sTILs between primary and metastatic lesions. A Cox proportional hazards model was used to determine if %sTILs in the breast tissue predicts time from primary tumor biopsy to diagnosis of brain metastasis (TTDBM) while adjusting for clinicopathologic features. Results: Average age at time of BCBM diagnosis was 53.6 (SD 12.3). 52% (34/66) of primary tumors were hormone receptor (HR) positive. Of 60 patients with known HER2 status, 28% (17) were HER2 positive and 40% (24) TNBC. Median %sTILS was significantly different between all primary tumors (15, IQR 5-20) and brain metastases (10, IQR 5-10), p = 0.001. The TNBC subtype (n = 11) showed the largest decrease in %sTILs between primary tumors (20, IQR 10-20) and brain metastases (5, IQR 5-10), p = 0.022. Comparing primary tumors and brain metastases, there was a 5% decrease in %sTILs in HR-/HER2+ (n = 5, p = 0.13) and HR+/HER2- (n = 7, p = 0.13), and a 5% increase in %sTILs in the HR+/Her2+ subtype (n = 9, p = 0.69). Percent sTILs in the primary tumors was not a significant predictor of TTDBM, when adjusting for race, age, HR status, and HER2 status, p = 0.87. Conclusions: BCBM have a significantly decreased %sTILs compared to their primary tumors, most prominent in TNBC. These results suggest altered tumor immunogenicity in the metastatic setting which has broad implications for the development of immunotherapy.

scholarly journals OTHR-09. Accelerating Research for Breast Cancer Brain Metastasis and Leptomeningeal Disease through Patient-led Collaborations

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii16-iii16
Author(s):  
Christine Hodgdon ◽  
Laurie Campbell
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Metastatic Breast ◽  
Basic Research ◽  
Leptomeningeal Disease ◽  
Eligibility Criteria ◽  
Cns Metastasis ◽  
Breast Cancer Brain Metastasis

Abstract Patient-driven Initiative of the Metastatic Breast Cancer (MBC) Alliance The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The Marina Project has grown to include 35members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or leptomeningeal disease (LMD). Disparities for Patients Living with BCBM & LMD In the US, approximately 200,000 new cases of brain metastases are diagnosed each year[1]. Approximately 10–15% of patients with MBC will develop brain metastases, and may be as high as 30–50% for certain subtypes[2]. A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research. Values and Objectives The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (i) Increase the quality and quantity of basic research; (ii) Increase the number of clinical trials in areas where research is lacking; (iii) Diversify the type of clinical trial interventions; (iv) Eliminate restrictive eligibility criteria in clinical trials; (v) Incorporate clinically meaningful trial endpoints [1] Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nature reviews. Clinical oncology vol. 8,6 (2011): 344–56. doi: 10.1038/nrclinonc.2011.58 [2] Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35

scholarly journals Ex vivo Evans blue assessment of the blood brain barrier in three breast cancer brain metastasis models

2014 ◽  
Vol 144 (1) ◽  
pp. 93-101 ◽  
Author(s):  
John Do ◽  
Deshka Foster ◽  
Corinne Renier ◽  
Hannes Vogel ◽  
Sahar Rosenblum ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Evans Blue ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Blood Brain ◽  
Breast Cancer Brain Metastasis ◽  
Metastasis Models

scholarly journals Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases

2019 ◽  
Vol 21 (11) ◽  
pp. 1401-1411 ◽  
Author(s):  
Franziska Maria Ippen ◽  
Julia Katharina Grosch ◽  
Megha Subramanian ◽  
Benjamin Macfarlane Kuter ◽  
Bianca M Liederer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cell Viability ◽  
Cell Lines ◽  
Akt Inhibitor ◽  
Activating Mutations ◽  
Breast Cancer Brain Metastasis ◽  
Breast Cancer Brain Metastases

Abstract Background Activating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43–70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood–brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model. Methods In in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)–mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry. Results GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model. Conclusions This study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.

INNV-02. ACCELERATING RESEARCH FOR BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL DISEASE THROUGH PATIENT-LED COLLABORATIONS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi105-vi105
Author(s):  
Christine Hodgdon
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Metastatic Breast ◽  
Basic Research ◽  
Leptomeningeal Disease ◽  
Eligibility Criteria ◽  
Cns Metastasis ◽  
Breast Cancer Brain Metastasis

Abstract PATIENT-DRIVEN INITIATIVE OF THE METASTATIC BREAST CANCER (MBC) ALLIANCE The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The project has grown to include 35 members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or LMD. DISPARITIES FOR PATIENTS LIVING WITH BCBM & LMD In the US, approximately 200,000 new cases of brain metastases are diagnosed each year.1 Approximately 10-15% of patients with MBC will develop brain metastases, and may be as high as 30-50% for certain subtypes.2 A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research. VALUES & OBJECTIVES The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (1) Increase the quality and quantity of basic research; (2) increase the number of clinical trials in areas where research is lacking; (3) diversify the type of clinical trial interventions; (4) eliminate restrictive eligibility criteria in clinical trials; (5) Incorporate clinically meaningful trial endpoints. References Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nat Rev. Clinical oncology vol. 8,6 (2011): 344-56. doi: 10.1038/nrclinonc.2011.58 Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35

Emerging Drugs for the Treatment of Breast Cancer Brain Metastasis: A Review of Patent Literature

2018 ◽  
Vol 13 (3) ◽  
pp. 348-359 ◽  
Author(s):  
Maricruz Anaya-Ruiz ◽  
Cindy Bandala ◽  
Patricia Martinez-Morales ◽  
Gerardo Landeta ◽  
Rebeca D. Martinez-Contreras ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Breast Cancer Brain Metastasis ◽  
Patent Literature

scholarly journals The Incidence of Brain Metastases Among Patients with Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Markus Kuksis ◽  
Yizhuo Gao ◽  
William Tran ◽  
Christianne Hoey ◽  
Alex Kiss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Triple Negative ◽  
Screening Program ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Breast Cancer Brain Metastasis

Abstract Background Patients with metastatic breast cancer (MBC) are living longer, but development of brain metastases often limits their survival. We conducted a systematic review and meta-analysis to determine the incidence of brain metastases in this patient population. Methods Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to: breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with HER2+, triple negative, and hormone receptor (HR)+/HER2- MBC; pooled overall estimates for incidence were calculated using random effects models. Results 937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2- MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0 – 34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5 – 40.6), and 15% among patients with HR+/HER2- MBC (median follow-up: 33.0 months, IQR: 31.9 – 36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10 – 0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09 – 0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03 – 0.08) for patients with HR+/HER2- MBC. Conclusion There is high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.

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