Systemic therapy following craniotomy in patients with a solitary breast cancer brain metastasis

AbstractBrian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

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RADT-03. OUTCOMES OF PATIENTS WITH HER2-POSITIVE BREAST CANCER METASTATIC TO BRAIN TREATED WITH HER2-TARGETED SYSTEMIC THERAPY AND STEREOTACTIC RADIOSURGERY

Neuro-Oncology ◽

10.1093/neuonc/noab196.161 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi41-vi41

Author(s):

John Shumway ◽

Marina Torras ◽

Katherine Reeder-Hayes ◽

Trevor Jolly ◽

Elizabeth Dees ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Stereotactic Radiosurgery ◽

Systemic Therapy ◽

Survival Outcomes ◽

Maximal Dimension ◽

Her2 Positive ◽

Intracranial Metastasis ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Abstract OBJECTIVE For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS). These include monoclonal antibodies such as trastuzumab (H) and pertuzumab (P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen. METHODS A single-institution retrospective review collected clinical data on patients with breast cancer metastatic to brain who were treated with SRS from 2009-2020. Statistical analyses were performed using the Kaplan-Meier method and chi-square statistic. RESULTS Of 82 patients with breast cancer metastatic to brain treated with SRS, 33 (40%) were HER2-positive, 18 of whom were hormone receptor-positive. At brain metastasis diagnosis, 15 patients (45%) had >1 intracranial metastasis (range 2-7), and the median brain metastasis maximal dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (T-DM1+/-HP, lapatinib+HP, chemotherapy+/-HP) followed by SRS at a median of 18.6 months after starting systemic therapy. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (multi-agent regimens, 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS (T-DM1+/-chemotherapy, lapatinib, HP, hormone therapy, chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups. Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS. CONCLUSION In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

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Application of fluorescein sodium in breast cancer brain-metastasis surgery

Cancer Management and Research ◽

10.2147/cmar.s176504 ◽

2018 ◽

Vol Volume 10 ◽

pp. 4325-4331 ◽

Cited By ~ 2

Author(s):

Shi-yin Xiao ◽

Ji Zhang ◽

Zheng-quan Zhu ◽

You-ping Li ◽

Wei-ying Zhong ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Fluorescein Sodium ◽

Breast Cancer Brain Metastasis

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Stereotactic Radiosurgery with Concurrent HER2-directed Therapy is Associated with Improved Objective Response for Breast Cancer Brain Metastasis

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2018.07.874 ◽

2018 ◽

Vol 102 (3) ◽

pp. e270

Author(s):

J.M. Kim ◽

J.A. Miller ◽

R. Kotecha ◽

S.T. Chao ◽

M. Ahluwalia ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Stereotactic Radiosurgery ◽

Objective Response ◽

Breast Cancer Brain Metastasis

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JAK2-binding long noncoding RNA promotes breast cancer brain metastasis

Journal of Clinical Investigation ◽

10.1172/jci91553 ◽

2017 ◽

Vol 127 (12) ◽

pp. 4498-4515 ◽

Cited By ~ 57

Author(s):

Shouyu Wang ◽

Ke Liang ◽

Qingsong Hu ◽

Ping Li ◽

Jian Song ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Breast Cancer Brain Metastasis

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Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis

10.1101/296384 ◽

2018 ◽

Cited By ~ 1

Author(s):

Soo-Hyun Kim ◽

Richard P. Redvers ◽

Lap Hing Chi ◽

Xiawei Ling ◽

Andrew J. Lucke ◽

...

Keyword(s):

Breast Cancer ◽

Mammary Gland ◽

Brain Metastasis ◽

Histone Deacetylase ◽

Clinical Relevance ◽

Histone Deacetylase Inhibitors ◽

Novel Therapies ◽

Breast Cancer Brain Metastasis ◽

The Brain

ABSTRACTBreast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.SUMMARY STATEMENTWe introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis and test novel therapies.

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CircBCBM1 Promotes Breast Cancer Brain Metastasis via miR-125a/BRD4 Axis

10.21203/rs.3.rs-130879/v1 ◽

2020 ◽

Author(s):

Bo Fu ◽

Wei Liu ◽

Peng Li ◽

Li Pan ◽

Ke Li ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Luciferase Reporter ◽

Circular Rnas ◽

Breast Cancer Patients ◽

Breast Cancer Brain Metastasis ◽

Tumorigenesis And Progression ◽

And Migration

Abstract Background: Accumulating evidence indicates that circular RNAs (circRNAs) play critical roles in tumorigenesis and progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown.Methods: In this reserch, we validated the expression and characterization of circBCBM1 through RT-qPCR, Sanger sequencing, RNase R assay and fluorescence in situ hybridization (FISH). Functional experiments were performed to determine the effect of circBCBM1 on growth and metastasis of 231-BR cells both in vitro and in vivo. The regulatory mechanisms among circBCBM1, miR-125a (has-miR-125a-5p), and BRD4 (bromodomain containing 4) were investigated by RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter assay and western blot. Results: Our findings demonstrated that circBCBM1 is a stable and cytoplasmic circRNA. Functionally, silencing of circBCBM1 led to decreased proliferation and migration of 231-BR cells whereas elevated circBCBM1 expression showed reverse effects in vitro. These findings were confirmed in vivo in mouse models, as knockdown of circBCBM1 significantly decreased growth and brain metastases of 231-BR cells. Mechanistically, circBCBM1 functions as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 expression and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, the overexpression of circBCBM1 in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients.Conclusions: These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis, which sheds light on the pathogenic mechanism of circBCBM1 and provides translational evidence that circBCBM1 may serve as a novel diagnostic or prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

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