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Cancers
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Breast Cancer Brain Metastasis and Leptomeningeal Disease
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Breast Cancer Brain Metastasis and Leptomeningeal Disease

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: closed (15 March 2025) | Viewed by 10688

Special Issue Editors

Dr. Albert Grinshpun

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Guest Editor
Dana-Farber Cancer Institute, Boston, MA, USA
Interests: metastatic breast cancer; molecular medicine; brain metastasis
Dr. Sarah Sammons

E-Mail Website
Guest Editor
Dana-Farber Cancer Institute, Boston, MA, USA
Interests: metastatic breast cancer; brain metastases
Dr. Nancy U. Lin

E-Mail Website
Guest Editor
1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
3. Harvard Medical School, Boston, MA, USA
Interests: metastatic breast cancer; brain metastases

Special Issue Information

Dear Colleagues,

Brain metastases are the most common intracranial malignancy. About one in five patients with metastatic breast cancer will develop brain metastases (BMs) during their disease course. Specifically, HER2-positive and triple-negative breast cancer subtypes have higher incidences of BMs, with recent data suggesting an increase in the overall incidence of MBC-related BMs in Western countries. Historically, BMs were associated with poor prognoses; however, novel approaches and therapies are starting to change the paradigm in patients with MBC-related BMs. Furthermore, BMs from metastatic breast cancer were found to have unique clinical and molecular features when compared to other tumor types, highlighting the need for further specific investment and research in this field.

Our goal in the current Special Issue of Cancers is to shed light on the latest advancements in this perplexing field and raise awareness of the most significant contemporary challenges in the diagnosis, monitoring, treatment, and prognostication of patients with metastatic breast cancer and BMs.

Dr. Albert Grinshpun
Dr. Sarah Sammons
Dr. Nancy U. Lin
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metastatic breast cancer
  • brain metastasis
  • leptomeninageal disease
  • diagnosis
  • monitoring
  • treatment

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Published Papers (6 papers)

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Research

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15 pages, 1236 KiB  
Article
Longitudinal CSF Tumor Cell Enumeration and Mutational Analysis as a Driver for Leptomeningeal Disease Management
by Arushi Tripathy, Pericles Corkos, Barbara Blouw, Deondra A. Montgomery, Melissa Moore, Marc H. Hedrick, Michael Youssef and Priya U. Kumthekar
Cancers 2025, 17(5), 825; https://doi.org/10.3390/cancers17050825 - 27 Feb 2025
Viewed by 713
Abstract
Background: Leptomeningeal disease (LMD) is challenging to diagnose and monitor given the poor sensitivity of current gold-standard diagnostics. Cerebrospinal fluid tumor cells (CSF-TCs) have been studied as a biomarker for disease management because oncogene amplification of the primary, metastatic, and CNS metastatic tumors [...] Read more.
Background: Leptomeningeal disease (LMD) is challenging to diagnose and monitor given the poor sensitivity of current gold-standard diagnostics. Cerebrospinal fluid tumor cells (CSF-TCs) have been studied as a biomarker for disease management because oncogene amplification of the primary, metastatic, and CNS metastatic tumors can be heterogeneous. The CNSide platform enumerates CSF-TCs and analyzes oncogene expression via immunocytochemistry (ICC), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS). We report the utility of this combined enumerative and mutational testing for LMD diagnosis and disease monitoring. Methods: A multicenter, retrospective analysis of commercially ordered assays from two health systems between January 2020 and July 2023 included 613 tests on 218 individual patients with suspected or confirmed LMD. To date, this is the largest cohort of patients in LMD literature evaluated using CSF-TCs. Results: CSF-TCs were detected in 67% (412/613) of samples. The most analyzed cancer types were breast (n = 105) and lung (n = 65). In lung cancer, anaplastic lymphoma kinase (ALK) was detected in 14% (17/118), and c-MET was detected in 61% (78/128). In breast cancer, HER2 was detected in 39% (65/168), and estrogen receptor (ER) was detected in 26% (44/168). Sixty-six patients underwent 2+ longitudinal CSF draws; among these, there were 58 flips in oncogene detection over time, and 30% (20/66) of patients had at least one biomarker change in the CSF. Conclusions: Longitudinal combined ICC/FISH/NGS CSF testing demonstrates a wide range in CSF-TC enumeration, which may be correlated with clinical course, and furthermore identifies actionable tumor markers that frequently fluctuate over time. Utilization of this platform would enable timely, personalized LMD-specific chemotherapy. Full article
(This article belongs to the Special Issue Breast Cancer Brain Metastasis and Leptomeningeal Disease)
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17 pages, 3063 KiB  
Article
Prognostic Factors in Therapy Regimes of Breast Cancer Patients with Brain Metastases: A Retrospective Monocentric Analysis
by Carolin Julia Curtaz, Judith Harms, Constanze Schmitt, Stephanie Tina Sauer, Sara Aniki Christner, Almuth Keßler, Achim Wöckel, Patrick Meybohm, Malgorzata Burek, Julia Feldheim and Jonas Feldheim
Cancers 2025, 17(2), 261; https://doi.org/10.3390/cancers17020261 - 15 Jan 2025
Viewed by 1054
Abstract
Background: Breast cancer patients who develop brain metastases have a high mortality rate and a massive decrease in quality of life. Approximately 10–15% of all patients with breast cancer (BC) and 5–40% of all patients with metastatic BC develop brain metastasis (BM) during [...] Read more.
Background: Breast cancer patients who develop brain metastases have a high mortality rate and a massive decrease in quality of life. Approximately 10–15% of all patients with breast cancer (BC) and 5–40% of all patients with metastatic BC develop brain metastasis (BM) during the course of the disease. However, there is only limited knowledge about prognostic factors in the treatment of patients with brain metastases in breast cancer (BMBC). Therefore, we retrospectively analyzed data of BMBC patients from the University Hospital of Würzburg for treatment patterns to find characteristics associated with a better or worse prognosis. These findings should help to treat the ever-increasing collective of patients with BMBC better in the future. Methods: The clinical data of 337 patients with cerebral metastatic breast cancer (date of death between 2004 and 2021) treated at the Department of Gynecology and Obstetrics of the University Hospital Würzburg were retrospectively analyzed, with a focus on patients’ survival. Results: The involvement of regional lymph nodes at initial diagnosis, the immunohistochemical subtype of TNBC at the onset of BMBC, and extracranial metastases at the time of BM diagnosis (bone, liver, lung metastases) were associated with a worse prognosis. In contrast, the immunohistochemical subtype of HER2/neu, the sole occurrence of a singular BM, the local surgical removal of BMs, and radiotherapy (especially stereotactic radiotherapy) were associated with prolonged survival. The number of therapies before the diagnosis of BMs also had a prognostic influence. Conclusions: Looking back at data is crucial for pinpointing risk elements affecting survival after a BM diagnosis. In our investigation, along with established factors like immunohistologic subtype, BM count, surgical excision, stereotactic irradiation, and type of extracranial metastasis, we also found that the number of therapies before BM diagnosis and the initial lymph node status were associated with patients’ survival. Potentially, these factors could be included in prospective prognostic scores for evaluating brain metastasis survival rates, thereby aiding in making appropriate treatment suggestions for impacted patients. Full article
(This article belongs to the Special Issue Breast Cancer Brain Metastasis and Leptomeningeal Disease)
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17 pages, 1126 KiB  
Article
Stereotactic Radiosurgery for Women Older than 65 with Breast Cancer Brain Metastases
by Rituraj Upadhyay, Brett G. Klamer, Haley K. Perlow, Julia R. White, Jose G. Bazan, Sachin R. Jhawar, Dukagjin M. Blakaj, John C. Grecula, Andrea Arnett, Mariella A. Mestres-Villanueva, Erin H. Healy, Evan M. Thomas, Arnab Chakravarti, Raju R. Raval, Maryam Lustberg, Nicole O. Williams, Joshua D. Palmer and Sasha J. Beyer
Cancers 2024, 16(1), 137; https://doi.org/10.3390/cancers16010137 - 27 Dec 2023
Cited by 4 | Viewed by 2045
Abstract
Background: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes [...] Read more.
Background: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. Methods: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan–Meier estimates and Cox proportional hazard regression method were used for survival analyses. Results: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65–84) compared to 52 years (31–64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated. Conclusions: Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients. Full article
(This article belongs to the Special Issue Breast Cancer Brain Metastasis and Leptomeningeal Disease)
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Review

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21 pages, 1288 KiB  
Review
Current Evidence in the Systemic Treatment of Brain Metastases from Breast Cancer and Future Perspectives on New Drugs, Combinations and Administration Routes: A Narrative Review
by Ornella Garrone, Fiorella Ruatta, Carmen Giusy Rea, Nerina Denaro, Michele Ghidini, Carolina Cauchi, Claudia Bareggi, Barbara Galassi, Marco C. Merlano and Roberto Rosenfeld
Cancers 2024, 16(24), 4164; https://doi.org/10.3390/cancers16244164 - 13 Dec 2024
Cited by 1 | Viewed by 2045
Abstract
Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the [...] Read more.
Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15–30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody–drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches. Full article
(This article belongs to the Special Issue Breast Cancer Brain Metastasis and Leptomeningeal Disease)
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15 pages, 684 KiB  
Review
Diagnostics and Screening in Breast Cancer with Brain and Leptomeningeal Metastasis: A Review of the Literature
by Adam J. Cohen-Nowak, Virginia B. Hill and Priya Kumthekar
Cancers 2024, 16(21), 3686; https://doi.org/10.3390/cancers16213686 - 31 Oct 2024
Viewed by 1792
Abstract
Brain and leptomeningeal metastases are complications of breast cancer with high rates of morbidity and mortality and have an estimated incidence of up to 30%. While National Comprehensive Cancer Network (NCCN) guidelines recommend screening for central nervous system metastasis in other neurotropic cancers [...] Read more.
Brain and leptomeningeal metastases are complications of breast cancer with high rates of morbidity and mortality and have an estimated incidence of up to 30%. While National Comprehensive Cancer Network (NCCN) guidelines recommend screening for central nervous system metastasis in other neurotropic cancers such as non-small cell lung cancer, there are no such recommendations for asymptomatic breast cancer patients at any stage of disease. This review highlights ongoing studies into screening and diagnostics for breast cancer with brain and leptomeningeal metastasis (BCBLM) as they relate to patient outcomes and prognostication. These include imaging methods such as MRI with novel contrast agents with or without PET/CT, as well as ‘liquid biopsy’ testing of the cerebrospinal fluid and serum to analyze circulating tumor cells, genomic material, proteins, and metabolites. Given recent advances in radiation, neurosurgery, and systemic treatments for BCBLM, screening for CNS involvement should be considered in patients with advanced breast cancer as it may impact treatment decisions and overall survival. Full article
(This article belongs to the Special Issue Breast Cancer Brain Metastasis and Leptomeningeal Disease)
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Other

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16 pages, 4264 KiB  
Systematic Review
Stereotactic Radiosurgery for Intracranial Breast Metastases: A Systematic Review and Meta-Analysis
by Neil D. Almeida, Cathleen Kuo, Tyler V. Schrand, Julia Rupp, Venkatesh S. Madhugiri, Victor Goulenko, Rohil Shekher, Chirag Shah and Dheerendra Prasad
Cancers 2024, 16(20), 3551; https://doi.org/10.3390/cancers16203551 - 21 Oct 2024
Cited by 1 | Viewed by 1678
Abstract
Background/Objectives: To determine the impact of stereotactic radiosurgery on outcomes of metastatic breast cancer with intracranial metastases. Methods: We systematically searched the PubMed and EMBASE databases for studies published between 1 January 1990 and 1 August 2024. Primary research articles evaluating the outcomes [...] Read more.
Background/Objectives: To determine the impact of stereotactic radiosurgery on outcomes of metastatic breast cancer with intracranial metastases. Methods: We systematically searched the PubMed and EMBASE databases for studies published between 1 January 1990 and 1 August 2024. Primary research articles evaluating the outcomes of stereotactic radiosurgery on intracranial metastases from breast cancer were included. Adverse events were defined as leptomeningeal disease, radiation necrosis, seizure, and headache. The pooled estimate was calculated using the DerSimonian and Laird approach. Results: Sixteen studies encompassing 1228 patients met the inclusion criteria. Our analysis revealed a median survival duration of 13.1 ± 3.8 months and a pooled 1-year overall survival rate of 53.1% after SRS treatment. There was a 29% local recurrence rate at 1 year and a 35% overall distant recurrence rate. In addition, our analysis found a relatively low rate of acute adverse events at 15.5%. Conclusions: SRS demonstrates promising efficacy and safety in managing intracranial metastases from breast cancer, with a favorable toxicity profile. Full article
(This article belongs to the Special Issue Breast Cancer Brain Metastasis and Leptomeningeal Disease)
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