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dc.contributor.authorO'Leary, B
dc.contributor.authorCutts, RJ
dc.contributor.authorLiu, Y
dc.contributor.authorHrebien, S
dc.contributor.authorHuang, X
dc.contributor.authorFenwick, K
dc.contributor.authorAndré, F
dc.contributor.authorLoibl, S
dc.contributor.authorLoi, S
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorCristofanilli, M
dc.contributor.authorHuang Bartlett, C
dc.contributor.authorTurner, NC
dc.date.accessioned2018-09-04T13:18:01Z
dc.date.issued2018-11
dc.identifier.citationCancer discovery, 2018, 8 (11), pp. 1390 - 1403
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2558
dc.identifier.eissn2159-8290en_US
dc.identifier.doi10.1158/2159-8290.cd-18-0264en_US
dc.description.abstractCDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor-positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA sequencing from 195 patients in the PALOMA-3 randomized phase III trial of palbociclib plus fulvestrant versus placebo plus fulvestrant. We show that clonal evolution occurs frequently during treatment, reflecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy. <i>RB1</i> mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, <i>P</i> = 0.041). New driver mutations emerged in <i>PIK3CA</i> (<i>P</i> = 0.00069) and <i>ESR1</i> after treatment in both arms, in particular <i>ESR1</i> Y537S (<i>P</i> = 0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on palbociclib plus fulvestrant but common in patients progressing later on treatment. These findings inform future treatment strategies to address resistance to palbociclib plus fulvestrant.<b>Significance:</b> Acquired mutations from fulvestrant are a major driver of resistance to fulvestrant and palbociclib combination therapy. <i>ESR1</i> Y537S mutation promotes resistance to fulvestrant. Clonal evolution results in frequent acquisition of driver mutations in patients progressing late on therapy, which suggests that early and late progression have distinct mechanisms of resistance. <i>Cancer Discov; 8(11); 1390-403. ©2018 AACR.</i> <i>See related commentary by Schiff and Jeselsohn, p. 1352</i> <i>This article is highlighted in the In This Issue feature, p. 1333</i>.
dc.formatPrint-Electronic
dc.format.extent1390 - 1403
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectPiperazines
dc.subjectPyridines
dc.subjectEstrogen Receptor alpha
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectPrognosis
dc.subjectFollow-Up Studies
dc.subjectDouble-Blind Method
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectFemale
dc.subjectClonal Evolution
dc.subjectBiomarkers, Tumor
dc.subjectFulvestrant
dc.titleThe Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial.
dc.typeJournal Article
dcterms.dateAccepted2018-09-06
rioxxterms.versionofrecord10.1158/2159-8290.cd-18-0264
rioxxterms.licenseref.startdate2018-11en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue11
pubs.notes6 months
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/Molecular Oncology
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/Molecular Oncology
pubs.publication-statusPublished
pubs.volume8en_US
pubs.embargo.terms6 months
icr.researchteamMolecular Oncologyen_US
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorGarcia-Murillas, Isaacen
dc.contributor.icrauthorO'Leary, Benjaminen


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