Cancers

Editorial

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2 pages, 156 KiB

Open AccessEditorial

Brain Metastasis in Breast Cancer Patients—Need for Improvement

by Isabell Witzel, Leticia Oliveira-Ferrer and Volkmar Müller

Cancers 2020, 12(11), 3190; https://doi.org/10.3390/cancers12113190 - 30 Oct 2020

Cited by 2 | Viewed by 1342

Abstract

The incidence of brain metastases (BM) in breast cancer patients is increasing [...] Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

Research

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12 pages, 1028 KiB

Open AccessArticle

Predicting Prognosis of Breast Cancer Patients with Brain Metastases in the BMBC Registry—Comparison of Three Different GPA Prognostic Scores

by Kerstin Riecke, Volkmar Müller, Rudolf Weide, Marcus Schmidt, Tjoung-Won Park-Simon, Volker Möbus, Christoph Mundhenke, Arkadius Polasik, Kristina Lübbe, Tobias Hesse, Elena Laakmann, Marc Thill, Peter A. Fasching, Carsten Denkert, Tanja Fehm, Valentina Nekljudova, Julia Rey, Sibylle Loibl and Isabell Witzel

Cancers 2021, 13(4), 844; https://doi.org/10.3390/cancers13040844 - 17 Feb 2021

Cited by 8 | Viewed by 2677

Abstract

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with [...] Read more.

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

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20 pages, 7046 KiB

Open AccessArticle

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

by Shailendra K. Gautam, Ranjana K. Kanchan, Jawed A. Siddiqui, Shailendra K. Maurya, Sanchita Rauth, Naveenkumar Perumal, Pranita Atri, Ramakanth C. Venkata, Kavita Mallya, Sameer Mirza, Moorthy P. Ponnusamy, Vimla Band, Sidharth Mahapatra, Maneesh Jain, Surinder K. Batra and Mohd Wasim Nasser

Cancers 2020, 12(10), 2838; https://doi.org/10.3390/cancers12102838 - 1 Oct 2020

Cited by 5 | Viewed by 3738

Abstract

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2⁺) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) [...] Read more.

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2⁺) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2⁺ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2⁺ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2⁺ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3⁺ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

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14 pages, 1143 KiB

Open AccessArticle

Characteristics and Clinical Outcome of Breast Cancer Patients with Asymptomatic Brain Metastases

by Elena Laakmann, Isabell Witzel, Tanja Neunhöffer, Rudolf Weide, Marcus Schmidt, Tjoung-Won Park-Simon, Volker Möbus, Christoph Mundhenke, Arkadius Polasik, Kristina Lübbe, Tobias Hesse, Kerstin Riecke, Marc Thill, Peter A. Fasching, Carsten Denkert, Tanja Fehm, Valentina Nekljudova, Julia Rey, Sibylle Loibl and Volkmar Müller

Cancers 2020, 12(10), 2787; https://doi.org/10.3390/cancers12102787 - 28 Sep 2020

Cited by 11 | Viewed by 2841

Abstract

Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM [...] Read more.

Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

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Review

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25 pages, 1042 KiB

Open AccessReview

Anti-Hormonal Therapy in Breast Cancer and Its Effect on the Blood-Brain Barrier

by Carolin J. Curtaz, Ludwig Kiesel, Patrick Meybohm, Achim Wöckel and Malgorzata Burek

Cancers 2022, 14(20), 5132; https://doi.org/10.3390/cancers14205132 - 19 Oct 2022

Cited by 2 | Viewed by 2973

Abstract

The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient [...] Read more.

The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

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19 pages, 1129 KiB

Open AccessReview

Molecular Mechanisms Associated with Brain Metastases in HER2-Positive and Triple Negative Breast Cancers

by Sarah Bryan, Isabell Witzel, Kerstin Borgmann and Leticia Oliveira-Ferrer

Cancers 2021, 13(16), 4137; https://doi.org/10.3390/cancers13164137 - 17 Aug 2021

Cited by 22 | Viewed by 3590

Abstract

Breast cancer (BC) is the most frequent cause of cancer-associated death for women worldwide, with deaths commonly resulting from metastatic spread to distant organs. Approximately 30% of metastatic BC patients develop brain metastases (BM), a currently incurable diagnosis. The influence of BC molecular [...] Read more.

Breast cancer (BC) is the most frequent cause of cancer-associated death for women worldwide, with deaths commonly resulting from metastatic spread to distant organs. Approximately 30% of metastatic BC patients develop brain metastases (BM), a currently incurable diagnosis. The influence of BC molecular subtype and gene expression on breast cancer brain metastasis (BCBM) development and patient prognosis is undeniable and is, therefore, an important focus point in the attempt to combat the disease. The HER2-positive and triple-negative molecular subtypes are associated with an increased risk of developing BCBM. Several genetic and molecular mechanisms linked to HER2-positive and triple-negative BC breast cancers appear to influence BCBM formation on several levels, including increased development of circulating tumor cells (CTCs), enhanced epithelial-mesenchymal transition (EMT), and migration of primary BC cells to the brain and/or through superior local invasiveness aided by cancer stem-like cells (CSCs). These specific BC characteristics, together with the ensuing developments at a clinical level, are presented in this review article, drawing a connection between research findings and related therapeutic strategies aimed at preventing BCBM formation and/or progression. Furthermore, we briefly address the critical limitations in our current understanding of this complex topic, highlighting potential focal points for future research. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

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21 pages, 339 KiB

Open AccessReview

Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies

by Alejandro Garcia-Alvarez, Andri Papakonstantinou and Mafalda Oliveira

Cancers 2021, 13(12), 2927; https://doi.org/10.3390/cancers13122927 - 11 Jun 2021

Cited by 56 | Viewed by 6747

Abstract

Development of brain metastases can occur in up to 30–50% of patients with breast cancer, representing a significant impact on an individual patient in terms of survival and quality of life. Patients with HER2-positive breast cancer have an increased risk of developing brain [...] Read more.

Development of brain metastases can occur in up to 30–50% of patients with breast cancer, representing a significant impact on an individual patient in terms of survival and quality of life. Patients with HER2-positive breast cancer have an increased risk of developing brain metastases; however, screening for brain metastases is not currently recommended due to the lack of robust evidence to support survival benefit. In recent years, several novel anti-HER2 agents have led to significant improvements in the outcomes of HER2-positive metastatic breast cancer. Despite these advances, brain and leptomeningeal metastases from HER2-positive breast cancer remain a significant cause of morbidity and mortality, and their optimal management remains an unmet need. This review presents an update on the current and novel treatment strategies for patients with brain metastases from HER2-positive breast cancer and discusses the open questions in the field. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

Other

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16 pages, 9580 KiB

Open AccessSystematic Review

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody–Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis

by Yan Wang, Hangcheng Xu, Yiqun Han, Yun Wu and Jiayu Wang

Cancers 2022, 14(14), 3372; https://doi.org/10.3390/cancers14143372 - 11 Jul 2022

Cited by 5 | Viewed by 2831

Abstract

HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a [...] Read more.

HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician’s choice of treatment (HR 0.17; 95% CrI 0.03–0.82) or afatinib (HR 0.14; 95% CrI 0.02–1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS. Full article

(This article belongs to the Special Issue Brain Metastasis in Breast Cancer)

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