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dc.contributor.authorChopra, Neha
dc.contributor.authorTovey, Holly
dc.contributor.authorPearson, Alex
dc.contributor.authorCutts, Ros
dc.contributor.authorToms, Christy
dc.contributor.authorProszek, Paula
dc.contributor.authorHubank, Michael
dc.contributor.authorDowsett, Mitch
dc.contributor.authorDodson, Andrew
dc.contributor.authorDaley, Frances
dc.contributor.authorKriplani, Divya
dc.contributor.authorGevensleben, Heidi
dc.contributor.authorDavies, Helen Ruth
dc.contributor.authorDegasperi, Andrea
dc.contributor.authorRoylance, Rebecca
dc.contributor.authorChan, Stephen
dc.contributor.authorTutt, Andrew
dc.contributor.authorSkene, Anthony
dc.contributor.authorEvans, Abigail
dc.contributor.authorBliss, Judith M
dc.contributor.authorNik-Zainal, Serena
dc.contributor.authorTurner, Nicholas C
dc.date.accessioned2020-04-06T23:30:44Z
dc.date.available2020-04-06T23:30:44Z
dc.date.issued2020-05-29
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/304149
dc.description.abstractTriple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll rights reserved
dc.subjectHumans
dc.subjectIndoles
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectRad51 Recombinase
dc.subjectRecombinational DNA Repair
dc.subjectTriple Negative Breast Neoplasms
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectPoly (ADP-Ribose) Polymerase-1
dc.subjectWhole Genome Sequencing
dc.subjectCirculating Tumor DNA
dc.titleHomologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2020
prism.publicationNameNat Commun
prism.startingPage2662
prism.volume11
dc.identifier.doi10.17863/CAM.51234
dcterms.dateAccepted2020-04-03
rioxxterms.versionofrecord10.1038/s41467-020-16142-7
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-05-29
dc.contributor.orcidPearson, Alex [0000-0002-5854-193X]
dc.contributor.orcidDegasperi, Andrea [0000-0001-6879-0596]
dc.contributor.orcidNik-Zainal, Serena [0000-0001-5054-1727]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (23916)
pubs.funder-project-idCancer Research UK (23433)
pubs.funder-project-idCancer Research UK (25274)
cam.issuedOnline2020-05-29


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