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dc.contributor.authorDowsett, M
dc.contributor.authorKilburn, L
dc.contributor.authorRimawi, MF
dc.contributor.authorOsborne, CK
dc.contributor.authorPogue-Geile, K
dc.contributor.authorLiu, Y
dc.contributor.authorJacobs, SA
dc.contributor.authorFinnigan, M
dc.contributor.authorPuhalla, S
dc.contributor.authorDodson, A
dc.contributor.authorMartins, V
dc.contributor.authorCheang, M
dc.contributor.authorPerry, S
dc.contributor.authorHolcombe, C
dc.contributor.authorTurner, NC
dc.contributor.authorSwift, C
dc.contributor.authorBliss, JM
dc.contributor.authorJohnston, S
dc.date.accessioned2021-11-23T14:13:11Z
dc.date.available2021-11-23T14:13:11Z
dc.date.issued2021-10-13
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2021
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4893
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-21-1628
dc.description.abstract<b>Purpose:</b> To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2- breast cancer; (ii) the pharmacodynamic effect of the agents on the biomarkers. <b>Experimental design:</b> 307 postmenopausal women with ER+/HER2- primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1 and CCND1. <b>Results:</b> Higher baseline ER and PgR were significantly associated with a greater chance of Complete Cell Cycle Arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumours showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumours showed CCCA 3-9 days after stopping palbociclib. <i>ESR1</i> mutations were found in 2/4 tumours for which surgery took place {greater than or equal to}6 months after starting treatment. <b>Conclusion:</b> High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3-9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the "off" week of its schedule.en_US
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.titleBiomarkers of response and resistance to palbociclib plus letrozole in patients with ER+/HER2- breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2021-10-07
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/1078-0432.ccr-21-1628
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2021-10-13
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.notesNot known
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamClinical Trials & Statistics Unit
dc.contributor.icrauthorKilburn, Lucyen_US
dc.contributor.icrauthorCheang, Chonen_US
dc.contributor.icrauthorBliss, Judithen_US


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