Title: OPTIMA: Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: Breast cancer deaths have fallen over the last 30 years from around half of all cases diagnosed to about a quarter due to post-surgical radiotherapy, endocrine treatment and chemotherapy. But, clinicians are concerned that many patients (especially those with the commonest ER-positive cancers) don’t benefit from chemotherapy and are being exposed unnecessarily to unpleasant side effects. The clinician’s dilemma is knowing who will benefit from chemotherapy and who can be safely spared. The OPTIMA trial will look at improving the selection of those patients who may benefit from chemotherapy using a test to determine who will have chemotherapy. These so called “multi-parameter” tests measure the activity of up to 100 genes in a tumour sample that are important in breast cancer to predict the risk of cancer recurrence. NICE evaluated four multi-parameter tests from 2011-13 and recommended that one (Oncotype DX) be made available for some NHS patients; NICE thought extra research was required on the other three. There is evidence that multi-parameter tests can also predict chemotherapy sensitivity but NICE considered that more research was needed on this topic. This question will be answered by OPTIMA. The OPTIMA trial will involve 4500 patients to look at the value of multi-parameter tests in the NHS. OPTIMA prelim, the feasibility study for the main trial, demonstrated that such a trial is possible and that patients can be recruited. The OPTIMA patient population will be at higher risk of relapse than those in the NICE evaluation because most will have cancer in their under-arm (axillary) lymph nodes. These patients are not eligible for NHS-funded Oncotype DX testing and would routinely be offered chemotherapy in addition to five or more years of endocrine therapy even if they may not benefit from the chemotherapy. Patients who consent to the trial will be randomised to standard management or to the test-directed treatment arm in which they will be assigned treatment (endocrine therapy with or without chemotherapy) according to the result of a Prosigna test performed on tumour tissue. Patients receiving chemotherapy will not know if they are on standard or test-directed treatment. Patients will be asked to donate spare tumour tissue for future research into gene tests. The main test used in OPTIMA prelim was Oncotype DX but other tests were evaluated to see which might offer the greatest value to the NHS. The value of Prosigna was shown to be higher than for the other tests, so this test will be used in the main OPTIMA trial. This is the biggest design change from OPTIMA prelim. Patients from OPTIMA prelim will be included in the final analysis. In order to show that test-directed treatment is safe, OPTIMA will compare the number of patients whose cancer returns within five years according to how their treatment was decided. The trial hypothesis is that there will be no more cancer recurrence with test-directed treatment compared with standard management. If this happens, OPTIMA will have shown that it is safe to use multi-parameter tests to make decisions about chemotherapy. The cost-effectiveness to the NHS of treating patients with chemotherapy in OPTIMA will be measured using information about the treatment given to patients collected from hospitals, questionnaires about the effect of treatment on family finance given to patients and information about long-term health of participants collected from central NHS databases.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS