The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer

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dc.check.date2021-02-14
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorSeltzer, Sean
dc.contributor.authorCorrigan, Mark
dc.contributor.authorO'Reilly, Seamus
dc.contributor.funderHealth Research Boarden
dc.date.accessioned2020-02-25T12:52:48Z
dc.date.available2020-02-25T12:52:48Z
dc.date.issued2020-02-14
dc.description.abstractBackground: de novo metastatic breast cancer (dnMBC) is responsible for 6–10% of breast cancer presentations with increasing incidence and has remained resistant to detection by mammography screening. Recent publications hypothesized that in addition to poor screening uptake, the presentation of dnMBC may be due to its unfavourable biology which remains unknown at the molecular level. Here we investigated the tumour biology of dnMBC in the form of clinicopathology, genomic alterations and differential gene expression to create a comparative landscape of de novo versus relapsed metastatic breast cancer (rMBC). Additionally, to address the current screening limitations, we conducted a preliminary biomarker investigation for early dnMBC detection. Methods: In this retrospective case-control study, gene expression and clinical data were accessed from the Cancer Genome Atlas (TCGA) for primary tumours of treatment-naïve patients with dnMBC (n = 17), rMBC (n = 49), and normal tissue (n = 113). The clinical and histological data were assessed categorically using Fisher's Exact-Test for significance (p < .05), or continuously using the Mann-Whitney Test (p < .05) where appropriate. The differential gene expression analysis was performed using EdgeR's negative binomial distribution model with a false discovery rate (FDR) <0.05. The resulting gene list was analysed manually for roles in metastasis as well as ontologically using STRING-DB with FDR <0.05. Results: dnMBCs showed improved median survival vs rMBC (36 vs. 12 months). dnMBCs were more likely to be hormone receptor positive, less likely to be triple negative with lower histological lymphocytic infiltrate. In terms of genome alterations, dnMBCs had 4-fold increased PTEN mutations and poor survival with ABL2 and GATA3 alterations. Expression-wise, dnMBCs down-regulated TNFa, IL-17 signalling, and chemotaxis, while up-regulating steroid biosynthesis, cell migration, and cell adhesion. Biomarker analysis detected pre-existing and novel breast cancer biomarkers. Conclusion: The comparative tumour landscape revealed significant clinical, pathological and molecular differences between dnMBC and rMBC, indicating that dnMBC may be a separate biological entity to rMBC at the primary level with differing paths to metastasis. Additionally, we provided a list of potential serum biomarkers that may be useful in detecting dnMBC in its pre-metastatic window if such a window exists.en
dc.description.sponsorshipHealth Research Board (Grant ID: SS-2018-129)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSeltzer, S., Corrigan, M. and O'Reilly, S. (2020) ‘The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer’, Experimental and Molecular Pathology, 114. doi: 10.1016/j.yexmp.2020.104404en
dc.identifier.doi10.1016/j.yexmp.2020.104404en
dc.identifier.eissn1096-0945
dc.identifier.issn0014-4800
dc.identifier.journaltitleExperimental and Molecular Pathologyen
dc.identifier.urihttps://hdl.handle.net/10468/9698
dc.identifier.volume114en
dc.language.isoenen
dc.publisherElsevier B.V.en
dc.rights© 2020, Elsevier Inc. All rights reserved. This manuscript version is made available under the CC BY-NC-ND 4.0 license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectBreast canceren
dc.subjectMetastasisen
dc.subjectGene expressionen
dc.subjectde novoen
dc.subjectBiomarkersen
dc.titleThe clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast canceren
dc.typeArticle (peer-reviewed)en
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