OPTIMA: a prospective randomised trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions


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Robert Stein1,Andreas Makris2,Luke Hughes-Davies3,Iain Macpherson4,Andrea Marshall5,Amy Campbell5,Peter Hall6,David Cameron6,Helena Earl7,Adele Francis8,Sarah Pinder9,Christopher Poole10,Daniel Rea11,John Bartlett12,Adrienne Morgan13,Leila Rooshenas14,Carmel Conefrey14,Jenny Donovan14,Claire Hulme15,Christopher McCabe16,Victoria Harmer17,Helen Higgins5,Janet Dunn5,On behalf of the OPTIMA Trial Management Group18
1National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK,2Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Middlesex, UK,3Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK,4University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK,5Warwick Clinical Trials Unit, University of Warwick, Coventry, UK,6University of Edinburgh, Edinburgh, UK,7University of Cambridge Department of Oncology and NIHR Cambridge Biomedical Research Centre, Cambridge, UK,8University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK,9Kings College London, Guy’s Hospital, London, UK,10University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK,11Cancer Research UK Institute for Cancer Studies, Birmingham, UK,12Ontario Institute for Cancer Research, Toronto, Canada,13Independent Cancer Patients' Voice, London, UK,14University of Bristol, Bristol, UK,15Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK,16Department of Emergency Medicine Research, University of Alberta, Edmonton, Canada,17Imperial College Healthcare Trust, London, UK,18Various

Abstract

Background

Multi-parameter gene expression assays (MPAs) are used to estimate individuals’ residual risk and guide chemotherapy use in hormone-sensitive HER2-negative node-negative early breast cancer. OPTIMA aims to prospectively validate the use of MPA testing to additionally predict chemotherapy sensitivity in a largely node-positive breast cancer population.

Method

OPTIMA is a partially blinded multi-centre, phase 3 RCT with an adaptive two-stage design. The preliminary phase (OPTIMA-prelim) evaluated the performance of MPAs for use in the main efficacy trial and assessed the feasibility and acceptability of a large UK trial. It demonstrated that a large-scale study is feasible in the UK. It showed that research on MPA-directed therapy, especially with Prosigna, should be of substantial value to the NHS. The OPTIMA patient population is women aged ≥40 years or men with resected early stage ER-positive, HER2-negative breast cancer, who have either 1-9 involved nodes or tumours ≥30mm. Randomisation is to standard management (chemotherapy then endocrine therapy) or MPA-directed treatment. Those with a tumour categorised as “high-risk” by the test have standard management whilst those at “low-risk” receive endocrine therapy alone. OPTIMA-prelim used Oncotype DX as the discriminator; OPTIMA uses Prosigna (PAM50). Co-primary outcomes are invasive disease free survival and cost-effectiveness. Tumour blocks from all consenting participants will be banked allowing the performance of alternative MPA technologies to be evaluated. An integrated qualitative study, undertaken with support from theme II of the MRC ConDuCT-II methodology hub, will aim to optimise recruitment and informed consent. A 4500 patient study allows the demonstration of 3% non-inferiority of MPA-directed treatment with 5% significance and 85% power. Inclusion of OPTIMA-prelim patients allows assessment of non-inferiority with 2.5% significance.

Results

Recruitment commenced in 2016.

Conclusion

OPTIMA is a prospective RCT validating MPA-directed therapy in node-positive hormone-sensitive early breast cancer and will have a global impact on patient treatment.