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.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 10/34/01. The contractual start date was in May 2012. The draft report began editorial review in May 2014 and was accepted for publication in September 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Robert C Stein reports grants from the NIHR-UCLH Biomedical Research Centre during the conduct of the study; grants and personal fees from Celgene Ltd and grants from Amgen Ltd outside the submitted work. Christopher Poole reports personal fees from Genomic Health outside the submitted work. Andreas Makris reports personal fees from Genomic Health during the conduct of the study. John MS Bartlett reports the following, all outside the submitted work: personal fees and other (support in kind) from BioNTech AG; personal fees from GE Healthcare; other (support in kind) from NanoString Technologies Inc.; other (support in kind) from Genoptix Medical Laboratory; grants from the NIHR HTA programme; grants from Cancer Research UK; grants from Celgene Ltd; grants from Ontario Institute for Cancer Research (OICR) High Impact Clinical Trials (HICT) Programme; grants from The Breast Cancer Research Foundation; grants from Medical Research Council; grants from Pfizer (UK); grants from Breakthrough Breast Cancer; grants from European Union; grants from The Breast Cancer Institute (UK); grants from European Organisation for Research and Treatment of Cancer; grants from Roche Pharmaceuticals Limited; personal fees from Daiichi Sankyo Pharma Development; and personal fees from Rexahn Pharmaceuticals Inc.