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

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

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.

scholarly journals A common goal to CARE: Cancer Advocates, Researchers, and Clinicians Explore current treatments and clinical trials for breast cancer brain metastases

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Natalie S. Joe ◽  
Christine Hodgdon ◽  
Lianne Kraemer ◽  
Kristin J. Redmond ◽  
Vered Stearns ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastases ◽  
Detection Methods ◽  
Future Research ◽  
Breast Cancer Brain Metastasis ◽  
Patient Advocates ◽  
Breast Cancer Brain Metastases ◽  
The Brain

AbstractBreast cancer is the most commonly diagnosed cancer in women worldwide. Approximately one-tenth of all patients with advanced breast cancer develop brain metastases resulting in an overall survival rate of fewer than 2 years. The challenges lie in developing new approaches to treat, monitor, and prevent breast cancer brain metastasis (BCBM). This review will provide an overview of BCBM from the integrated perspective of clinicians, researchers, and patient advocates. We will summarize the current management of BCBM, including diagnosis, treatment, and monitoring. We will highlight ongoing translational research for BCBM, including clinical trials and improved detection methods that can become the mainstay for BCBM treatment if they demonstrate efficacy. We will discuss preclinical BCBM research that focuses on the intrinsic properties of breast cancer cells and the influence of the brain microenvironment. Finally, we will spotlight emerging studies and future research needs to improve survival outcomes and preserve the quality of life for patients with BCBM.

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.

scholarly journals ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Sara Charmsaz ◽  
Ben Doherty ◽  
Sinéad Cocchiglia ◽  
Damir Varešlija ◽  
Attilio Marino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
In Silico ◽  
Ex Vivo ◽  
Metastatic Breast ◽  
Peptide Mimetic ◽  
Breast Cancer Brain Metastasis

Abstract Background Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. Methods Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target’s natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. Results Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. Conclusion ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

scholarly journals Differential expression of the G0/G1 switch gene 2, G0S2, in the brain metastases of patients with breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Differential Expression ◽  
Treatment Options ◽  
Metastatic Breast ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Breast Cancer Brain Metastasis ◽  
Microarray Datasets ◽  
The Brain

In patients with breast cancer, brain metastasis provides limited treatment options (1-3). To discover genes associated with brain metastases in patients with metastatic breast cancer, we mined published microarray datasets, comparing global transcription in brain metastases and primary tumors of the breast (4, 5). Using this methodology, we identified significant differential expression of the G0/G1 switch gene 2, encoded by G0S2, in the brain metastases of patients with breast cancer as compared to primary tumors of the breast. The G0S2 gene product could be of relevance to any one of the numerous processes by which tumor cells in breast cancer metastasize, including exit of the breast, entry into the periphery, breach of the blood brain barrier or colonization of and survival in the brain.

scholarly journals Glucose Transporter 3 Is Essential for the Survival of Breast Cancer Cells in the Brain

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1568 ◽  
Author(s):  
Min-Hsun Kuo ◽  
Wen-Wei Chang ◽  
Bi-Wen Yeh ◽  
Yeh-Shiu Chu ◽  
Yueh-Chun Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Glucose Transporter ◽  
Metastatic Breast ◽  
Breast Cancer Brain Metastasis ◽  
The Brain

Breast cancer brain metastasis commonly occurs in one-fourth of breast cancer patients and is associated with poor prognosis. Abnormal glucose metabolism is found to promote cancer metastasis. Moreover, the tumor microenvironment is crucial and plays an active role in the metabolic adaptations and survival of cancer cells. Glucose transporters are overexpressed in cancer cells to increase glucose uptake. The glucose transporter 3 (GLUT3) is a high-affinity glucose transporter that is highly expressed in mammalian neurons. GLUT3 is also overexpressed in several malignant brain tumors. However, the role of GLUT3 in breast cancer brain metastasis remains unknown. The results of the present study demonstrated that GLUT3 is highly overexpressed in brain metastatic breast cancers and mediates glucose metabolic reprogramming. Furthermore, knockdown of cAMP-response element binding protein (CREB) could directly regulate GLUT3 expression in brain metastatic breast cancer cells. Notably, we verified and provided a novel role of GLUT3 in mediating glucose metabolism and assisting breast cancer cells to survive in the brain to promote brain metastasis.

scholarly journals Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hanna Huebner ◽  
Christian M. Kurbacher ◽  
Geoffrey Kuesters ◽  
Andreas D. Hartkopf ◽  
Michael P. Lux ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Menopausal Status ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Patient Characteristics ◽  
Breast Cancer Patients ◽  
Patient Identification ◽  
Eligibility Criteria

Abstract Background Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. Methods Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. Results Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. Conclusion Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. Trial registration Clinicaltrials, NCT02338167, Registered 14 January 2015 - retrospectively registered.

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 Apelin is differentially expressed in brain metastatic breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Microarray Data ◽  
Metastatic Breast ◽  
Clinical Problem ◽  
Differentially Expressed ◽  
Gene Encoding ◽  
The Brain

Brain metastases are a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to discover genes associated with brain metastasis in patients with brain metastatic breast cancer. We found that the gene encoding the peptide apelin, APLN, was among those most differentially expressed in the brain metastases of patients with brain metastatic breast cancer. APLN may be of relevance to the biology underlying metastasis to the brain in humans with metastatic breast cancer.

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