Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors

AbstractDue to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.Key messageWe quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the “my choice” HRD score in collaboration with Myriad Genetics.These confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.

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Abstract PD13-01: Homologous recombination deficiency represents a new therapeutic strategy for breast cancer brain metastases

10.1158/1538-7445.sabcs20-pd13-01 ◽

2021 ◽

Author(s):

Nicola S Cosgrove ◽

Damir Varešlija ◽

Stephen Keelan ◽

Simon Furney ◽

Jodi M Carter ◽

...

Keyword(s):

Breast Cancer ◽

Homologous Recombination ◽

Brain Metastases ◽

Therapeutic Strategy ◽

Homologous Recombination Deficiency ◽

Breast Cancer Brain Metastases

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Genomic profiling of breast cancer brain metastases reveals targetable alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.2525 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 2525-2525

Author(s):

Sheheryar Kairas Kabraji ◽

Liam F. Spurr ◽

Melissa E Hughes ◽

Yvonne Y. Li ◽

Jose Pablo Leone ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Copy Number ◽

Enrichment Analysis ◽

Fisher Exact Test ◽

Copy Number Alterations ◽

Genomic Alterations ◽

Primary Tumors ◽

Significant Difference ◽

Breast Cancer Brain Metastases

2525 Background: Genomic characterization of breast cancer brain metastases (BCBMs) has thus far been limited. The objective of this study was to describe the landscape of genomic alterations in patients (pts) with BCBMs. Methods: Targeted next-generation DNA sequencing of > 300 cancer-related genes (OncoPanel) was prospectively performed on primary and metastatic (met) tumors in 321 pts with a diagnosis of BCBM between August 2016 and April 2019 at Dana-Farber Cancer Institute (table). Enrichment analysis of genomic alterations was performed using a two-sided Fisher exact test and differences in tumor mutation burden (TMB) between groups were assessed using two-sided Mann-Whitney U test. Multiple comparison correction was performed using the Benjamini-Hochberg procedure. Results: All subtypes were represented in BCBM (25 HR+/HER2-; 24 HR+/HER2+; 27 HR-/HER2+; 18 TNBC; 5 unknown; n = 99) and extracranial (EC) samples: (96 HR+/HER2-; 32 HR+/HER2+; 22 HR-/HER2+; 41 TNBC; 31 unknown; n = 222). BCBMs were found most commonly to have mutations or copy number alterations in TP53, ERBB2, PIK3CA, GATA3, PTEN, ESR1, CDH1, BRCA2, ARID1A, BRCA1 (>5% frequency, table). Two pts acquired ERBB2 amplification (amp) between the matched primary breast sample and brain met. In pair-wise comparisons of BCBMs to unmatched primaries or EC mets, only ERBB2 amp was significantly enriched (table, † = adjusted p < 0.05). There was no significant difference in TMB between BCBM and EC mets (median 9.12 vs 7.26, p = 0.15). In contrast, TMB was significantly higher in BCBMs compared to unmatched primaries (median 9.12 vs 7.26, p=0.005). Conclusions: BCBMs display similar mutations and copy number alterations compared to primary tumors and EC mets in pts with BCBM. These data suggest that BCBMs contain actionable genomic alterations that are most often also reflected in EC disease. Alterations in ERBB2, PIK3CA/PTEN, and BRCA1/2 represent potentially targetable alterations in pts with BCBM. [Table: see text]

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Subtype switching in breast cancer brain metastases: a multicenter analysis

Neuro-Oncology ◽

10.1093/neuonc/noaa013 ◽

2020 ◽

Vol 22 (8) ◽

pp. 1173-1181 ◽

Cited By ~ 8

Author(s):

Alexander F C Hulsbergen ◽

An Claes ◽

Vasileios K Kavouridis ◽

Ali Ansaripour ◽

Claudine Nogarede ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Growth Factor Receptor ◽

Hazard Ratio ◽

Receptor Expression ◽

Her2 Status ◽

Primary Tumors ◽

Pathology Reports ◽

Breast Cancer Brain Metastases ◽

Extracranial Metastases

Abstract Background Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM. Methods BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed. Results In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio = 1.80, P = 0.03). Patients gaining HER2 status (n = 8) showed a nonsignificant tendency toward improved survival (hazard ratio = 0.64, P = 0.17). Conclusions In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.

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Myocyte Enhancer Factor 2C as a New Player in Human Breast Cancer Brain Metastases

Cells ◽

10.3390/cells10020378 ◽

2021 ◽

Vol 10 (2) ◽

pp. 378

Author(s):

Sofia Galego ◽

Linda Azevedo Kauppila ◽

Rui Malhó ◽

José Pimentel ◽

Maria Alexandra Brito

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Disease Severity ◽

Nuclear Translocation ◽

Nuclear Staining ◽

Ki 67 ◽

Primary Tumors ◽

Myocyte Enhancer Factor ◽

Breast Cancer Brain Metastases ◽

Enhancer Factor

Myocyte enhancer factor 2C (MEF2C) is increasingly expressed in mice along with breast cancer brain metastases (BCBM) development. We aim to ascertain MEF2C expression in human BCBM, establish the relationship with disease severity, disclose the involvement of vascular endothelial growth factor receptor-2 (VEGFR-2) and β-catenin, also known as KDR and CTNNB1, respectively, and investigate if matched primary tumors express the protein. We studied resected BCBM for the expression of MEF2C, VEGFR-2, and ß-catenin, as well as proliferation (Ki-67) and epithelial (pan Cytokeratin) markers, and related experimental and clinical data. MEF2C expression was further assessed in matched primary tumors and non-BCBM samples used as controls. MEF2C expression was observed in BCBM, but not in controls, and was categorized into three phenotypes (P): P1, with extranuclear location; P2, with extranuclear and nuclear staining, and P3, with nuclear location. Nuclear translocation increased with metastases extension and Ki-67-positive cells number. P1 was associated with higher VEFGR-2 plasma membrane immunoreactivity, whereas P2 and P3 were accompanied by protein dislocation. P1 was accompanied by β-catenin membrane expression, while P2 and P3 exhibited β-catenin nuclear translocation. Primary BC samples expressed MEF2C in mammary ducts and scattered cells in the parenchyma. MEF2C emerges as a player in BCBM associated with disease severity and VEGFR-2 and β-catenin signaling.

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