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Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives: To establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. Design: This was a Phase III randomised controlled non-inferiority trial. Setting: The setting was 152 NHS hospitals. Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. Intervention: Randomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment. Main outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p

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. Objectives: 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. Design: Partially blinded RCT with adaptive design. Setting: Thirty-five UK hospitals. Participants: 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. Interventions: 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. Main outcome measures: 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. Trial registration: Current Controlled Trials ISRCTN42400492. Funding: 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.