Systemic therapy for brain metastases

Rick, Jonathan W.; Shahin, Maryam; Chandra, Ankush; Ore, Cecilia Dalle; Yue, John K.; Nguyen, Alan; Yagnik, Garima; Sagar, Soumya; Arfaie, Saman; Aghi, Manish K.

doi:10.1016/j.critrevonc.2019.07.012

Cited by 48 publications

(39 citation statements)

References 67 publications

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“…Brain metastases (BM) are the most common intracranial malignancy in adults (1). Breast cancer is the second leading cause of metastases to the central nervous system (CNS), including the brain and leptomeninges (2)(3)(4). Evidence of increasing intracranial recurrences in patients with metastatic breast cancer (MBC) is likely because of improved systemic treatment of extracranial disease leading to prolonged survival and higher intracranial disease detection rates (3).…”

Section: Introductionmentioning

confidence: 99%

“…Breast cancer is the second leading cause of metastases to the central nervous system (CNS), including the brain and leptomeninges (2)(3)(4). Evidence of increasing intracranial recurrences in patients with metastatic breast cancer (MBC) is likely because of improved systemic treatment of extracranial disease leading to prolonged survival and higher intracranial disease detection rates (3). Prognosis after CNS recurrence varies by subtype and involvement, with 4-month estimated median survival in patients with leptome-ningeal metastases (LM) and 3.4-to 25.0-month median survival in patients with predominantly parenchymal intracranial disease, depending on graded prognostic assessment scores (5,6).…”

Section: Introductionmentioning

confidence: 99%

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A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

Tolaney

Sahebjam

Rhun

et al. 2020

Clinical Cancer Research

142

103

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The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor-positive (HR þ) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety. Patients and Methods: This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype-specific cohorts AD: A (HR þ , HER2 À MBC), B (HR þ , HER2 þ MBC), C (HR þ MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design. Results: In cohort A (n ¼ 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0-10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1-35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3-16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B (n ¼ 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0-23.0) was observed. Median OS was 10.1 months (95% CI, 4.2-14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C (n ¼ 10), one confirmed complete parenchymal response was observed. In cohort D (n ¼ 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96-[cyclindependent kinase 4 (CDK4)] and 19-fold (CDK6) above in vitro IC 50. Safety was consistent with prior studies. Conclusions: This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR þ , HER2 À MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclibbased combinations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

Tolaney

Sahebjam

Rhun

et al. 2020

Clinical Cancer Research

142

103

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“…Wholebrain radiotherapy is frequently used in patients with multiple brain metastases. Furthermore, modern systemic treatment options such as immunotherapy including checkpoint inhibitors and targeted therapy are increasingly used to control intra-and extracranial disease (6,7). Importantly, some molecularly defined subgroups of patients have been identified which have an improved prognosis (8) and benefit from these recently developed agents, e.g., combined BRAF/MEK inhibition using the kinase inhibitors dabrafenib plus trametinib in patients with BRAF-mutant melanoma brain metastases (9).…”

Section: Introductionmentioning

confidence: 99%

PET/MRI Radiomics in Patients With Brain Metastases

et al. 2020

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Although a variety of imaging modalities are used or currently being investigated for patients with brain tumors including brain metastases, clinical image interpretation to date uses only a fraction of the underlying complex, high-dimensional digital information from routinely acquired imaging data. The growing availability of high-performance computing allows the extraction of quantitative imaging features from medical images that are usually beyond human perception. Using machine learning techniques and advanced statistical methods, subsets of such imaging features are used to generate mathematical models that represent characteristic signatures related to the underlying tumor biology and might be helpful for the assessment of prognosis or treatment response, or the identification of molecular markers. The identification of appropriate, characteristic image features as well as the generation of predictive or prognostic mathematical models is summarized under the term radiomics. This review summarizes the current status of radiomics in patients with brain metastases.

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“…However, appearance of metastases also means that a level of systemic tumour disease was reached and therefore describes a palliative situation. Overall, about 10-15% of the breast cancer patients develop cerebral metastases, one of the most severe metastases types, which is associated with a very poor prognosis with only 20% one-year survival [18].…”

Section: Introductionmentioning

confidence: 99%

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

Curtaz

Schmitt

Herbert

et al. 2020

Fluids Barriers CNS

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Background: The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods: We adapted and validated the CD34 + cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results: The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion: We demonstrate that the CD34 + cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with

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Systemic therapy for brain metastases

Cited by 48 publications

References 67 publications

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer

PET/MRI Radiomics in Patients With Brain Metastases

Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood–brain barrier model

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