title: OPTIMA prelim: a randomised feasibility study of personalised care in the treatment of women with early breast cancer.
abstract: BACKGROUND
  There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype. The assays provide prognostic information and have been claimed to predict chemotherapy sensitivity. There is a dearth of prospective validation studies. The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) is the feasibility phase of a randomised controlled trial (RCT) designed to validate the use of multiparameter assay directed chemotherapy decisions in the NHS.
  
  
  OBJECTIVE
  OPTIMA prelim was designed to establish the acceptability to patients and clinicians of randomisation to test-driven treatment assignment compared with usual care and to select an assay for study in the main RCT.
  
  
  METHODS
  Partially blinded RCT with adaptive design.
  
  
  METHODS
  Thirty-five UK hospitals.
  
  
  METHODS
  Patients aged ≥ 40 years with surgically treated ER-positive HER2-negative primary breast cancer and with 1-9 involved axillary nodes, or, if node negative, a tumour at least 30 mm in diameter.
  
  
  METHODS
  Randomisation between two treatment options. Option 1 was standard care consisting of chemotherapy followed by endocrine therapy. In option 2, an Oncotype DX(®) test (Genomic Health Inc., Redwood City, CA, USA) performed on the resected tumour was used to assign patients either to standard care [if 'recurrence score' (RS) was > 25] or to endocrine therapy alone (if RS was ≤ 25). Patients allocated chemotherapy were blind to their randomisation.
  
  
  METHODS
  The pre-specified success criteria were recruitment of 300 patients in no longer than 2 years and, for the final 150 patients, (1) an acceptance rate of at least 40%; (2) recruitment taking no longer than 6 months; and (3) chemotherapy starting within 6 weeks of consent in at least 85% of patients.
  
  
  RESULTS
  Between September 2012 and 3 June 2014, 350 patients consented to join OPTIMA prelim and 313 were randomised; the final 150 patients were recruited in 6 months, of whom 92% assigned chemotherapy started treatment within 6 weeks. The acceptance rate for the 750 patients invited to participate was 47%. Twelve out of the 325 patients with data (3.7%, 95% confidence interval 1.7% to 5.8%) were deemed ineligible on central review of receptor status. Interviews with researchers and recordings of potential participant consultations made as part of the integral qualitative recruitment study provided insights into recruitment barriers and led to interventions designed to improve recruitment. Patient information was changed as the result of feedback from three patient focus groups. Additional multiparameter analysis was performed on 302 tumour samples. Although Oncotype DX, MammaPrint(®)/BluePrint(®) (Agendia Inc., Irvine, CA, USA), Prosigna(®) (NanoString Technologies Inc., Seattle, WA, USA), IHC4, IHC4 automated quantitative immunofluorescence (AQUA(®)) [NexCourse BreastTM (Genoptix Inc. Carlsbad, CA, USA)] and MammaTyper(®) (BioNTech Diagnostics GmbH, Mainz, Germany) categorised comparable numbers of tumours into low- or high-risk groups and/or equivalent molecular subtypes, there was only moderate agreement between tests at an individual tumour level (kappa ranges 0.33-0.60 and 0.39-0.55 for tests providing risks and subtypes, respectively). Health economics modelling showed the value of information to the NHS from further research into multiparameter testing is high irrespective of the test evaluated. Prosigna is currently the highest priority for further study.
  
  
  CONCLUSIONS
  OPTIMA prelim has achieved its aims of demonstrating that a large UK clinical trial of multiparameter assay-based selection of chemotherapy in hormone-sensitive early breast cancer is feasible. The economic analysis shows that a trial would be economically worthwhile for the NHS. Based on the outcome of the OPTIMA prelim, a large-scale RCT to evaluate the clinical effectiveness and cost-effectiveness of multiparameter assay-directed chemotherapy decisions in hormone-sensitive HER2-negative early breast would be appropriate to take place in the NHS.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN42400492.
  
  
  BACKGROUND
  This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 10. See the NIHR Journals Library website for further project information. The Government of Ontario funded research at the Ontario Institute for Cancer Research. Robert C Stein received additional support from the NIHR University College London Hospitals Biomedical Research Centre.
authors: Department of Oncology, University College London Hospitals, London, UK.
authors: Robert C
authors: RC
authors: Stein
authors: Warwick Medical School, University of Warwick, Coventry, UK.
authors: Janet A
authors: JA
authors: Dunn
authors: Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors: John M S
authors: JM
authors: Bartlett
authors: Warwick Medical School, University of Warwick, Coventry, UK.
authors: Amy F
authors: AF
authors: Campbell
authors: Warwick Medical School, University of Warwick, Coventry, UK.
authors: Andrea
authors: A
authors: Marshall
authors: Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK.
authors: Peter
authors: P
authors: Hall
authors: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: Leila
authors: L
authors: Rooshenas
authors: Independent Cancer Patients' Voice, London, UK.
authors: Adrienne
authors: A
authors: Morgan
authors: Warwick Medical School, University of Warwick, Coventry, UK.
authors: Christopher
authors: C
authors: Poole
authors: Research Oncology, Division of Cancer Studies, King's College London, London, UK.
authors: Sarah E
authors: SE
authors: Pinder
authors: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors: David A
authors: DA
authors: Cameron
authors: Warwick Medical School, University of Warwick, Coventry, UK.
authors: Nigel
authors: N
authors: Stallard
authors: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors: Jenny L
authors: JL
authors: Donovan
authors: Department of Emergency Medicine, University of Alberta, Edmonton, AB, Canada.
authors: Christopher
authors: C
authors: McCabe
authors: Oncology Centre, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundations Trust, Cambridge, UK.
authors: Luke
authors: L
authors: Hughes-Davies
authors: Department of Clinical Oncology, Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, UK.
authors: Andreas
authors: A
authors: Makris
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D012107:Research Design; D006113:United Kingdom
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human