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dc.contributor.authorHrebien, S
dc.contributor.authorCiti, V
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorCutts, R
dc.contributor.authorFenwick, K
dc.contributor.authorKozarewa, I
dc.contributor.authorMcEwen, R
dc.contributor.authorRatnayake, J
dc.contributor.authorMaudsley, R
dc.contributor.authorCarr, TH
dc.contributor.authorde Bruin, EC
dc.contributor.authorSchiavon, G
dc.contributor.authorOliveira, M
dc.contributor.authorTurner, N
dc.date.accessioned2019-08-20T09:19:52Z
dc.date.issued2019-06
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2019, 30 (6), pp. 945 - 952
dc.identifier.issn0923-7534
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3324
dc.identifier.eissn1569-8041
dc.identifier.doi10.1093/annonc/mdz085
dc.description.abstractBackground Dynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy.Patients and methods Patients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort.Results In the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P = 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083-0.50, P < 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P = 0.904) nor in the PIK3CA mutant subpopulation (P = 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS.Conclusion Early on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development.Clinical registration number NCT01625286.
dc.formatPrint
dc.format.extent945 - 952
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectNeoplasm Metastasis
dc.subjectPaclitaxel
dc.subjectPyrimidines
dc.subjectPyrroles
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectPrognosis
dc.subjectSurvival Rate
dc.subjectCohort Studies
dc.subjectFollow-Up Studies
dc.subjectDouble-Blind Method
dc.subjectFemale
dc.subjectRandomized Controlled Trials as Topic
dc.subjectClinical Trials, Phase I as Topic
dc.subjectClinical Trials, Phase II as Topic
dc.subjectBiomarkers, Tumor
dc.subjectCirculating Tumor DNA
dc.subjectProgression-Free Survival
dc.titleEarly ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial.
dc.typeJournal Article
rioxxterms.versionofrecord10.1093/annonc/mdz085
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc/4.0
rioxxterms.licenseref.startdate2019-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncology
pubs.issue6
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.volume30
pubs.embargo.termsNo embargo
icr.researchteamMolecular Oncologyen_US
dc.contributor.icrauthorGarcia-Murillas, Isaacen
dc.contributor.icrauthorTurner, Nicholasen


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