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dc.contributor.authorO'Leary, B
dc.contributor.authorCutts, RJ
dc.contributor.authorHuang, X
dc.contributor.authorHrebien, S
dc.contributor.authorLiu, Y
dc.contributor.authorAndré, F
dc.contributor.authorLoibl, S
dc.contributor.authorLoi, S
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorCristofanilli, M
dc.contributor.authorBartlett, CH
dc.contributor.authorTurner, NC
dc.date.accessioned2020-07-03T11:19:56Z
dc.date.issued2020-06-17
dc.identifier.citationJournal of the National Cancer Institute, 2020
dc.identifier.issn0027-8874
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3797
dc.identifier.eissn1460-2105
dc.identifier.doi10.1093/jnci/djaa087
dc.description.abstractBackground There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i.Methods PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided.Results Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed.Conclusions Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleCirculating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer.
dc.typeJournal Article
dcterms.dateAccepted2020-06-09
rioxxterms.versionofrecord10.1093/jnci/djaa087
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-06-17
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of the National Cancer Institute
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/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.embargo.termsNo embargo
icr.researchteamMolecular Oncologyen_US
dc.contributor.icrauthorO'Leary, Benjaminen
dc.contributor.icrauthorGarcia-Murillas, Isaacen
dc.contributor.icrauthorTurner, Nicholasen


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