title: Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial.
abstract: BACKGROUND
  The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer.
  
  
  METHODS
  In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m(2) once every 21 days) followed by three cycles of fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), and cyclophosphamide (500 mg/m(2)) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235).
  
  
  RESULTS
  Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18-27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13-21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]).
  
  
  CONCLUSIONS
  Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and overall survival outcomes is unknown and will be reported after longer follow-up. Meta-analysis of available neoadjuvant trials is likely to be the only way to define subgroups of early breast cancer that would have clinically significant long-term benefit from bevacizumab treatment.
  
  
  BACKGROUND
  Cancer Research UK, Roche, Sanofi-Aventis.
authors.affiliation: University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, and Cambridge Breast Cancer Research Unit Cambridge, Cambridge, UK. Electronic address: hme22@cam.ac.uk.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Dunn
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Blenkinsop
authors.affiliation: Cambridge Clinical Trials Unit-Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Grybowicz
authors.affiliation: Cambridge Clinical Trials Unit-Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, UK.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vallier
authors.affiliation: University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, and Cambridge Breast Cancer Research Unit Cambridge, Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Western General Hospital, Edinburgh, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Thomas
authors.affiliation: NIHR Cambridge Biomedical Research Centre, and Cambridge Breast Cancer Research Unit Cambridge, Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Hughes-Davies
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gounaris
authors.affiliation: Peterborough City Hospital, Edith Cavell Campus, Peterborough, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: McAdam
authors.affiliation: Nottingham University Hospital (City Campus), Nottingham, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: West Middlesex University Hospital, Isleworth, UK.
authors.forename: Rizvana
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: Royal Bournemouth Hospital, Bournemouth University, Bournemouth, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Hickish
authors.affiliation: The Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Houston
authors.affiliation: City Hospital, Dudley Road, Birmingham, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rea
authors.affiliation: Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada; Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bartlett
authors.affiliation: University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, and Cambridge Breast Cancer Research Unit Cambridge, Cambridge, UK; Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Cameron
authors.affiliation: Western General Hospital, Edinburgh, UK.
authors.forename: Larry
authors.initials: L
authors.lastname: Hayward
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C508053:ERBB2 protein, human