Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorCOLEMAN, Robert
dc.contributor.authorFINKELSTEIN, Dianne M.
dc.contributor.authorBARRIOS, Carlos
dc.contributor.authorMARTIN, Miguel
dc.contributor.authorIWATA, Hiroji
dc.contributor.authorHEGG, Roberto
dc.contributor.authorGLASPY, John
dc.contributor.authorPERIANEZ, Alvaro Montano
dc.contributor.authorTONKIN, Katia
dc.contributor.authorDELEU, Ines
dc.contributor.authorSOHN, Joohyuk
dc.contributor.authorCROWN, John
dc.contributor.authorDELALOGE, Suzette
dc.contributor.authorDAI, Tian
dc.contributor.authorZHOU, Ying
dc.contributor.authorJANDIAL, Danielle
dc.contributor.authorCHAN, Arlene
dc.date.accessioned2020-01-21T15:11:20Z
dc.date.available2020-01-21T15:11:20Z
dc.date.issued2020
dc.description.abstractBackground Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. Method In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged >= 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154. Findings Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0.97, 95% CI 0.82-1.14; p=0.70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. Interpretation Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer.eng
dc.description.indexMEDLINEeng
dc.description.sponsorshipAmgenAmgen
dc.identifier.citationLANCET ONCOLOGY, v.21, n.1, p.60-72, 2020
dc.identifier.doi10.1016/S1470-2045(19)30687-4
dc.identifier.eissn1474-5488
dc.identifier.issn1470-2045
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/34462
dc.language.isoeng
dc.publisherELSEVIER SCIENCE INCeng
dc.relation.ispartofLancet Oncology
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright ELSEVIER SCIENCE INCeng
dc.subject.otherzoledronic acideng
dc.subject.otherclinical-practiceeng
dc.subject.otherhigh-riskeng
dc.subject.otherbisphosphonateseng
dc.subject.otherefficacyeng
dc.subject.otherproliferationeng
dc.subject.othermetastaseseng
dc.subject.othersafetyeng
dc.subject.wosOncologyeng
dc.titleAdjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trialeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryEspanha
hcfmusp.affiliation.countryJapão
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryBélgica
hcfmusp.affiliation.countryCoréia do Sul
hcfmusp.affiliation.countryIrlanda
hcfmusp.affiliation.countryFrança
hcfmusp.affiliation.countryAustrália
hcfmusp.affiliation.countryisokr
hcfmusp.affiliation.countryisogb
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisoes
hcfmusp.affiliation.countryisojp
hcfmusp.affiliation.countryisoca
hcfmusp.affiliation.countryisobe
hcfmusp.affiliation.countryisoie
hcfmusp.affiliation.countryisofr
hcfmusp.affiliation.countryisoau
hcfmusp.author.externalCOLEMAN, Robert:Univ Sheffield, Dept Oncol & Metab, Sheffield S10 2SJ, S Yorkshire, England
hcfmusp.author.externalFINKELSTEIN, Dianne M.:Massachusetts Gen Hosp, Boston, MA 02114 USA
hcfmusp.author.externalBARRIOS, Carlos:Pontificia Univ Catolica Rio Grande do Sul, Hosp Sao Lucas, Ctr Pesquisa Oncol, Porto Alegre, RS, Brazil
hcfmusp.author.externalMARTIN, Miguel:Univ Complutense, Inst Invest Sanitaria Gregorio Maranon, Ciberonc, Geicam, Madrid, Spain
hcfmusp.author.externalIWATA, Hiroji:Aichi Canc Ctr Hosp, Nayoya, Japan
hcfmusp.author.externalGLASPY, John:Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA
hcfmusp.author.externalPERIANEZ, Alvaro Montano:Hosp Univ Virgen del Rocio, Seville, Spain
hcfmusp.author.externalTONKIN, Katia:Cross Canc Inst, Edmonton, AB, Canada
hcfmusp.author.externalDELEU, Ines:AZ Nikolass, Ctr Oncol, St Niklaas, Belgium
hcfmusp.author.externalSOHN, Joohyuk:Yonsei Univ, Coll Med, Severance Hosp, Seoul, South Korea
hcfmusp.author.externalCROWN, John:All Ireland Cooperat Oncol Res Grp, Dublin, Ireland
hcfmusp.author.externalDELALOGE, Suzette:Inst Gustave Roussy, Villejuif, France
hcfmusp.author.externalDAI, Tian:Amgen Inc, Thousand Oaks, CA 91320 USA
hcfmusp.author.externalZHOU, Ying:Amgen Inc, Thousand Oaks, CA 91320 USA
hcfmusp.author.externalJANDIAL, Danielle:Amgen Inc, Thousand Oaks, CA 91320 USA
hcfmusp.author.externalCHAN, Arlene:Curtin Univ, Breast Canc Res Ctr Western Australia, Perth, WA, Australia; Curtin Univ, Sch Med, Perth, WA, Australia
hcfmusp.citation.scopus160
hcfmusp.contributor.author-fmusphcROBERTO HEGG
hcfmusp.description.beginpage60
hcfmusp.description.endpage72
hcfmusp.description.issue1
hcfmusp.description.volume21
hcfmusp.origemWOS
hcfmusp.origem.pubmed31806543
hcfmusp.origem.scopus2-s2.0-85077170429
hcfmusp.origem.wosWOS:000505211900054
hcfmusp.publisher.cityNEW YORKeng
hcfmusp.publisher.countryUSAeng
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