The genomic landscape of breast cancer brain metastases: a systematic review

Morgan, Alexander James; Giannoudis, Athina; Palmieri, Carlo

doi:10.1016/s1470-2045(20)30556-8

Cited by 71 publications

(93 citation statements)

References 50 publications

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“…The searches on the ClinicalTrials.gov were performed for Breast Cancer, Recruiting, Active (not recruiting), Completed, Adult and selecting for speci c gene mutations/alterations for PIK3CA, AKT1, ESR1, ERBB2/HER2 and TP53. Similar work on BCBM mutated genes was recently presented by our group in a systematic review [13].…”

Section: Data Analysis and Statisticssupporting

confidence: 67%

“…Forty-three clinical trials are currently available for BC patients with mutations in these 5 genes as identi ed within ClinicalTrials.gov (Supplementary Table 4) whereas twelve trials speci cally recruiting patients with BCBM using targeted-therapies for the identi ed gene mutations/alterations were recently reported [13]. Drugs targeting PIK3CA [Paxalicib (GDC-0084), Buparlisib (BMK120)], ERBB2/HER2 (Neratinib, Afatinib, Pyrotinib, Tucatinib), pathways and/or genes involved in the cell cycle (Abemaciclib, NKTR-102) are currently undergoing assessment in clinical trials either as single agents or in combination with standard of care treatments for BCBM [13].…”

Section: Actionability Of Mutated Genesmentioning

confidence: 99%

“…Genomic pro ling has also demonstrated the complex and diverse molecular landscapes of secondary metastatic BCs [6,7,10,11]. BM sequencing studies have identi ed differences in their mutational landscape as compared to primary tumours [12][13][14][15][16]. The identi cation of genomic alterations within BM and the use of targeted therapies against these mutations may improve the clinical outcomes of patients with BCBM [9][10][11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Genomic Profiling Using The UltraSEEK Panel Identifies Discordancy Between Paired Primary And Breast Cancer Brain Metastases And An Association With Brain Metastasis-Free Survival

Palmieri

Giannoudis

Sartori

et al. 2021

Preprint

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Purpose. Brain metastases (BM) are an increasing clinical problem. This study aimed to assess paired primary breast cancers (BC) and BM for aberrations within TP53, PIK3CA, ESR1, ERBB2 and AKT utilising the MassARRAY® UltraSEEK® technology (Agena Bioscience, San Diego, USA). Methods. DNA isolated from 32 paired primary BCs and BMs was screened using the custom UltraSEEK® Breast Cancer Panel. Data acquisition and analysis was performed by the Agena Bioscience Typer software v4.0.26.74. Results. Mutations were identified in 91% primary BCs and 88% BM cases. TP53, AKT1, ESR1, PIK3CA and ERBB2 genes were mutated in 68.8%, 37.5%, 31.3%, 28.1% and 3.1% respectively of primary BCs and in 59.4%, 37.5%, 28.1%, 28.1% and 3.1% respectively of BMs. Differences in the mutations within the 5 genes between BC and paired BM were identified in 62.5% of paired cases. In primary BCs, ER-positive/HER2-negative cases harboured the most mutations (70%), followed by ER-positive/HER2-positive (15%) and triple-negatives (13.4%) whereas in BMs, the highest number of mutations was observed in triple-negatives (52.5%), followed by ER-positive/HER2-negative (35.6%) and ER-negative/HER2-positive (12%). There was a significant association between the number of mutations in the primary BC and breast-to-brain metastasis-free survival (p=0.0001) but not with overall survival (p=0.056). Conclusion. These data demonstrate the discordancy between primary BC and BM, as well as the presence of clinically important, actionable mutations in BCBM. The UltraSEEK® Breast Cancer Panel provides a tool for BCBM that can be utilised to direct more tailored treatment decisions and for clinical studies investigating targeted agents.

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Section: Data Analysis and Statisticssupporting

confidence: 67%

Section: Actionability Of Mutated Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genomic Profiling Using The UltraSEEK Panel Identifies Discordancy Between Paired Primary And Breast Cancer Brain Metastases And An Association With Brain Metastasis-Free Survival

Palmieri

Giannoudis

Sartori

et al. 2021

Preprint

Self Cite

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“…The hypothesis assumes that compatibility between the biological characteristics of the cancer cells (‘seeds’) and the microenvironment of the metastatic site (‘soil’) plays an important role in cancer metastasis. Some key molecules for this phenomenon in breast cancer metastasis have been reported ( 26 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

Cerebellar preference of luminal A and B type and basal ganglial preference of HER2‑positive type breast cancer‑derived brain metastases

et al. 2021

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The purpose of the current study was to investigate the hypothesis that the spatial distribution of brain metastases could be affected by the biological subtypes of breast cancer. CT (n=1) or MRI (n=66) images of 67 patients with a total of 437 treatment-naive brain metastases from breast cancer were retrospectively reviewed. Patients were grouped according to the biological subtype of the tumor [luminal A, 28; luminal B, 9; human epidermal growth factor receptor 2 (HER2) positive, 14; triple-negative breast cancer (TNBC), 16]. All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. The distribution pattern of brain metastases after image standardization was analyzed. The cerebellum and the frontal lobe were more commonly affected by breast cancer brain metastases. Brain metastases from luminal A and B types of breast cancer arose more often in the cerebellum. Brain metastases from HER2-positive type breast cancer occurred more often in the putamen and the thalamus and less frequently in the cerebellum than other types (P=0.0057). The subtypes of breast cancer are related to differences in the spatial distributions of their brain metastases. These differences may be utilized to plan different cranial irradiation strategies according to the breast cancer subtypes.

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“…The XRCC4 protein of the non-homologous end-joining repair pathway, the ERCC1 protein of base excision repair, and the TOPO1 gene associated with repair at replication forks also showed increased expression in BM compared to primary BCs [69,70]. A recent review article identified 268 mutated genes in BM involved in breast cancer-related signaling pathways, regulation of gene transcription, the cell cycle, and DNA repair [71]. Genetic alterations in both activators of the DNA damage response-ATR (Ataxia telangiectasiarelated) [72] and ATM (Ataxia telangiectasia-mutated) [73]-were more frequently detected in BM compared with primary BCs and metastases from other sites, respectively.…”

Section: Dna Repair Mechanisms In Bcbm-survival In the Brain Microenvironmentmentioning

confidence: 99%

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

Bryan

Witzel

Borgmann

et al. 2021

Cancers

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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.

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The genomic landscape of breast cancer brain metastases: a systematic review

Cited by 71 publications

References 50 publications

Genomic Profiling Using The UltraSEEK Panel Identifies Discordancy Between Paired Primary And Breast Cancer Brain Metastases And An Association With Brain Metastasis-Free Survival

Genomic Profiling Using The UltraSEEK Panel Identifies Discordancy Between Paired Primary And Breast Cancer Brain Metastases And An Association With Brain Metastasis-Free Survival

Cerebellar preference of luminal A and B type and basal ganglial preference of HER2‑positive type breast cancer‑derived brain metastases

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

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