Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities

Cosgrove, Nicola; Varešlija, Damir; Keelan, Stephen; Elangovan, Ashuvinee; Atkinson, Jennifer M.; Cocchiglia, Sinéad; Bane, Fiona T.; Singh, Vikram; Furney, Simon J.; Hu, Chunling; Carter, Jodi M.; Hart, Steven N.; Yadav, Siddhartha; Goetz, Matthew P.; Hill, A. D. K.; Oesterreich, Steffi; Lee, Adrian V.; Couch, Fergus J.; Young, Leonie S.

doi:10.1038/s41467-022-27987-5

Cited by 51 publications

(51 citation statements)

References 70 publications

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“…5b and Supplementary Table 18 ). Analysis of the cohort of patients with breast cancer brain metastases 59 , 60 who were treated with radiotherapy confirmed the correlation between S100A9 expression levels and survival from brain metastasis diagnosis (Fig. 5e and Supplementary Table 16 ), which was reproduced by S100A8 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 56%

“…5a ), potentially suggesting that a specific subtype of melanoma brain metastases, not represented by available mouse models, could be the main contributor to S100A9 positivity. To score the clinical correlation with S100A9, several cohorts of patients with brain metastasis and lung cancer ( n = 22), breast cancer 59 , 60 ( n = 42) or melanoma ( n = 34) were selected based on the presence of patients who received neurosurgery followed by radiotherapy (Fig. 5a and Supplementary Tables 15 – 17 ).…”

Section: Resultsmentioning

confidence: 99%

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Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Monteiro¹,

Miarka²,

Perea-García³

et al. 2022

Nat Med

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Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Monteiro¹,

Miarka²,

Perea-García³

et al. 2022

Nat Med

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“…The PDO-PDOX approach to study BCBM metastases is an alternative promising approach for generating efficient BCBM preclinical models that have not yet been exploited. Recently, Cosgrove et al demonstrated that freshly resected BCBM tumours could be used to generate PDO and perform genomic and transcriptomic analysis to identify therapeutic vulnerabilities [123].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Models of Brain Metastases in Breast Cancer

et al. 2022

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Breast cancer remains a leading cause of mortality among women worldwide. Brain metastases confer extremely poor prognosis due to a lack of understanding of their specific biology, unique physiologic and anatomic features of the brain, and limited treatment strategies. A major roadblock in advancing the treatment of breast cancer brain metastases (BCBM) is the scarcity of representative experimental preclinical models. Current models are predominantly based on the use of animal xenograft models with immortalized breast cancer cell lines that poorly capture the disease’s heterogeneity. Recent years have witnessed the development of patient-derived in vitro and in vivo breast cancer culturing systems that more closely recapitulate the biology from individual patients. These advances led to the development of modern patient-tissue-based experimental models for BCBM. The success of preclinical models is also based on the imaging technologies used to detect metastases. Advances in animal brain imaging, including cellular MRI and multimodality imaging, allow sensitive and specific detection of brain metastases and monitoring treatment responses. These imaging technologies, together with novel translational breast cancer models based on patient-derived cancer tissues, represent a unique opportunity to advance our understanding of brain metastases biology and develop novel treatment approaches. This review discusses the state-of-the-art knowledge in preclinical models of this disease.

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“…MMR testing could be used in clinical practice to help guide treatment based on immunotherapy, particularly in HER2 enriched and TN tumors as we found these to be more proportionally involved by MMR. Also, mutational signatures associated with MMR have been found to be enriched in breast cancer brain metastases compared to primary breast tumors 45 . Suggesting there may be a role of MMR and PD-L1 testing in metastatic breast cancer specimens.…”

Section: Discussionmentioning

confidence: 99%

MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Unique Proteomic Networks and Variable Clinical Significance

Hacking

Chou

Baykara

et al. 2022

Preprint

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Mismatch repair (MMR) alterations are important prognostic and predictive biomarkers in a variety of cancer subtypes including colorectal and endometrial. However, in breast cancer (BC), the distinction and clinical significance of MMR is largely unknown. This may be due in part to the fact that genetic alterations in MMR genes are rare, and only seen to occur in around 3% of BCs. In the present study we analyzed TCGA data using a multi-sample protein-protein interactions (PPI) analysis tool, Proteinarium, and showed a distinct separation in the MMR deficient and intact specific networks. MMR deficient tumor specific networks have a highly connected cluster of histone genes, identified by unique PPI. We also found that distribution of MMR deficient breast cancer is more prevalent in HER2-enriched and triple-negative (TN) BC subtypes compared to luminal BCs. Poorer survival was seen in patients with HER2-enriched BCs with MMR deficiency, whereas an improved survival was seen in TNBCs with MMR deficiency. We recommend defining MMR deficient breast cancer by next generation sequencing (NGS) when any somatic mutation is detected in one of the 7 MMR genes found in our study. Our recommendations include labeling patients with variants of undetermined significance (VUS) as MMR deficient supported by findings from distinct clusters of patients based on our network analysis. MMR may have a role in guiding the use of immunotherapy for both TN as well as HER2-enriched BC.

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Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities

Cited by 51 publications

References 70 publications

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Preclinical Models of Brain Metastases in Breast Cancer

MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Unique Proteomic Networks and Variable Clinical Significance

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