OPTIMA: Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis

The OPTIMA trial seeks to advance the development of personalised medicine in breast cancer by prospectively validating the use of multi-parameter tests in the management of primary breast cancer. It is normal clinical practice to offer adjuvant chemotherapy to women with estrogen receptor (ER) positive, HER2-negative primary breast cancer who have axillary lymph node involvement to reduce the risk of subsequent relapse. Conventional histopathology does not reliably identify which patients within this population are likely to benefit from chemotherapy. Multi-parameter assays of tumour gene expression have been shown to provide superior prognostic information to grade assessed by histopathology. Multi-parameter assays may also be able to predict chemotherapy sensitivity. This was recommended as a topic for future research in the 2013 NICE DG10 guidelines. The question will be answered by OPTIMA. The target population is similar to that included in the DG10 evaluation but most will have axillary node involvement and are therefore not eligible for NHS-funded Oncotype DX testing. Eligible patients will be offered randomisation to one of two management options consisting of either the standard management, which is chemotherapy followed by endocrine therapy, or test-directed treatment. Patients randomised to test-directed treatment will have a Prosigna test performed on a tumour block. Those with a tumour categorised as “high-risk” by the test will be assigned to standard management whilst those at “low-risk” will be treated with endocrine therapy alone. Patients allocated chemotherapy will be blinded to their randomisation to reduce the risk of bias arising from non-compliance with the protocol. Prosigna was selected on the basis of the analysis of OPTIMA prelim, the feasibility phase of OPTIMA, which used Oncotype DX to decide treatment. Five additional multi-parameter tests were evaluated in the OPTIMA prelim population. Analysis of this data suggested that the value of information to the NHS from further research into Prosigna is likely to be particularly high. The primary outcome of OPTIMA is non-inferiority of invasive disease-free survival (IDFS). This is a surrogate for overall survival, a 2º endpoint, which is the accepted relevant clinical outcome for the effectiveness of chemotherapy use in primary breast cancer. The experience of OPTIMA prelim suggests that it is feasible to recruit 4500 patients over four years. OPTIMA will have the ability to demonstrate 3% non-inferiority of the test-directed treatment, with 5% significance and 85% power. The addition of patients from OPTIMA prelim will allow non-inferiority to be assessed with a 2.5% significance level. Two economic analyses will take place: (1) within trial cost-effectiveness analyses and (2) a lifetime decision analytical cost-effectiveness model. The base-case analysis for both will take the perspective of the NHS and personal social services. Analyses from a societal perspective will also be conducted. Patients participating in OPTIMA will be asked to donate tissue blocks which will form an invaluable resource for future research into genomic assays and chemotherapy sensitivity in breast cancer.