Show simple item record

dc.contributor.authorMehra, N
dc.contributor.authorDolling, D
dc.contributor.authorSumanasuriya, S
dc.contributor.authorChristova, R
dc.contributor.authorPope, L
dc.contributor.authorCarreira, S
dc.contributor.authorSeed, G
dc.contributor.authorYuan, W
dc.contributor.authorGoodall, J
dc.contributor.authorHall, E
dc.contributor.authorFlohr, P
dc.contributor.authorBoysen, G
dc.contributor.authorBianchini, D
dc.contributor.authorSartor, O
dc.contributor.authorEisenberger, MA
dc.contributor.authorFizazi, K
dc.contributor.authorOudard, S
dc.contributor.authorChadjaa, M
dc.contributor.authorMacé, S
dc.contributor.authorde Bono, JS
dc.date.accessioned2018-04-12T10:30:24Z
dc.date.issued2018-09
dc.identifier.citationEuropean urology, 2018, 74 (3), pp. 283 - 291
dc.identifier.issn0302-2838
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1642
dc.identifier.eissn1873-7560
dc.identifier.doi10.1016/j.eururo.2018.02.013
dc.description.abstractBACKGROUND:Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. OBJECTIVE:To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. DESIGN, SETTING, AND PARTICIPANTS:Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. RESULTS AND LIMITATIONS:In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p=0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p=0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p=0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. CONCLUSIONS:We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. PATIENT SUMMARY:In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.
dc.formatPrint-Electronic
dc.format.extent283 - 291
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectNeoplasm Metastasis
dc.subjectTaxoids
dc.subjectKallikreins
dc.subjectProstate-Specific Antigen
dc.subjectAntineoplastic Agents, Phytogenic
dc.subjectTreatment Outcome
dc.subjectDrug Administration Schedule
dc.subjectProspective Studies
dc.subjectTime Factors
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectProstatic Neoplasms, Castration-Resistant
dc.subjectBiomarkers, Tumor
dc.subjectCirculating Tumor DNA
dc.subjectDocetaxel
dc.subjectProgression-Free Survival
dc.titlePlasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA).
dc.typeJournal Article
dcterms.dateAccepted2018-02-12
rioxxterms.versionofrecord10.1016/j.eururo.2018.02.013
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEuropean urology
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.publication-statusPublished
pubs.volume74
pubs.embargo.termsNo embargo
icr.researchteamCancer Biomarkersen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorDolling, Daviden
dc.contributor.icrauthorSumanasuriya, Seminien
dc.contributor.icrauthorSeed, Georgeen
dc.contributor.icrauthorCarreira, Suzanneen
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorHall, Emmaen


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0