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dc.contributor.authorPearson, A
dc.contributor.authorProszek, P
dc.contributor.authorPascual, J
dc.contributor.authorFribbens, C
dc.contributor.authorShamsher, MK
dc.contributor.authorKingston, B
dc.contributor.authorO'Leary, B
dc.contributor.authorHerrera-Abreu, MT
dc.contributor.authorCutts, RJ
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorBye, H
dc.contributor.authorWalker, BA
dc.contributor.authorGonzalez De Castro, D
dc.contributor.authorYuan, L
dc.contributor.authorJamal, S
dc.contributor.authorHubank, M
dc.contributor.authorLopez-Knowles, E
dc.contributor.authorSchuster, EF
dc.contributor.authorDowsett, M
dc.contributor.authorOsin, P
dc.contributor.authorNerurkar, A
dc.contributor.authorParton, M
dc.contributor.authorOkines, AFC
dc.contributor.authorJohnston, SRD
dc.contributor.authorRing, A
dc.contributor.authorTurner, NC
dc.date.accessioned2019-10-14T09:29:08Z
dc.date.issued2020-02
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (3), pp. 608 - 622
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3381
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-18-4044
dc.description.abstractPurpose Advanced breast cancer (ABC) has not been subjected to the same degree of molecular scrutiny as early primary cancer. Breast cancer evolves with time and under the selective pressure of treatment, with the potential to acquire mutations with resistance to treatment and disease progression. To identify potentially targetable mutations in advanced breast cancer, we performed prospective molecular characterization of a cohort of patients with ABC.Experimental design Biopsies from patients with advanced breast cancer were sequenced with a 41 genes targeted panel in the ABC Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumor DNA (ctDNA) analysis, along with matched primary tumor to assess for acquisition in ABC in a subset of patients.Results We sequenced 210 ABC samples, demonstrating enrichment compared with primary disease for potentially targetable mutations in HER2 (in 6.19% of samples), AKT1 (7.14%), and NF1 (8.10%). Of these enriched mutations, we show that NF1 mutations were frequently acquired in ABC, not present in the original primary disease. In ER-positive cancer cell line models, loss of NF1 resulted in endocrine therapy resistance, through both ER-dependent and -independent mechanisms. NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors in vitro . Patients with NF1 mutations detected in baseline circulating tumor DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant.Conclusions Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of NF1 mutations.
dc.formatPrint-Electronic
dc.format.extent608 - 622
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectPiperazines
dc.subjectPyridines
dc.subjectCyclin D1
dc.subjectNeurofibromin 1
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectTreatment Outcome
dc.subjectProspective Studies
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectFulvestrant
dc.titleInactivating <i>NF1</i> Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance.
dc.typeJournal Article
dcterms.dateAccepted2019-10-02
rioxxterms.versionofrecord10.1158/1078-0432.ccr-18-4044
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2020-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue3
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/17/18 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/17/18 Starting Cohort
pubs.publication-statusPublished
pubs.volume26
pubs.embargo.termsNo embargo
icr.researchteamEndocrine Therapy Resistanceen_US
icr.researchteamMolecular Oncologyen_US
icr.researchteamEndocrinologyen_US
icr.researchteamTranslational Genomicsen_US
dc.contributor.icrauthorSchuster, Eugeneen
dc.contributor.icrauthorPascual, Javieren
dc.contributor.icrauthorGarcia-Murillas, Isaacen
dc.contributor.icrauthorPearson, Alexen
dc.contributor.icrauthorHubank, Michaelen
dc.contributor.icrauthorKingston, Belindaen
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorLopez Knowles, Elenaen
dc.contributor.icrauthorDowsett, Mitchen
dc.contributor.icrauthorO'Leary, Benjaminen


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