Optima: Optimal personalised treatment of early breast cancer using multi-parameter analysis, an international randomized trial of tumor gene expression test-directed chemotherapy treatment in a largely node-positive population

Background: 
Multi-parameter tumor gene expression assays (MPAs) are validated tools to assist adjuvant chemotherapy decisions for post-menopausal women with luminal-type node-negative breast cancer. Currently there is less certainty for women with 1-3 involved axillary lymph nodes and no information on MPA use for patients with higher level nodal involvement. Three RCTs with available data report chemotherapy benefit for premenopausal women; with limited use of ovarian function suppression (OFS) for non-chemotherapy treated participants, chemotherapy-induced menopause may explain these results. 
Methods: 
OPTIMA is an international academic, partially-blinded RCT of test-directed chemotherapy treatment with an adaptive design. Women and men aged 40 or older with resected luminal-type breast cancer may participate if they fulfil one of the following stage criteria: pN1-2; pN1mi with pT ≥20mm; pN0 with pT ≥30mm. Consenting patients are randomized between standard treatment with chemotherapy followed by endocrine therapy or to undergo Prosigna testing; those with high-Prosigna Score ( > 60) tumors receive standard treatment whilst those with low-score tumors are treated with endocrine therapy alone. Patients are informed only of their treatment; test details, and randomization for chemotherapy-treated patients are masked. Clinical choice of chemotherapy is declared at randomization from a menu of standard regimens. Endocrine therapy must be for at least 5 years. Women postmenopausal at trial entry should receive an AI; men, tamoxifen; and premenopausal women, either an AI or tamoxifen, and OFS for 3 or more years; OFS initiation may be deferred because of post-chemotherapy amenorrhea. OPTIMA aims to randomize 2250 patients in each arm to demonstrate non-inferiority of test directed treatment, defined as not more than 3% below the estimated 85% 5-year IDFS for the control arm with a one sided 5% significance level. Power is 81% assuming recruitment over 96-months from January 2017 and 12 months minimum follow-up. OPTIMA also has at least 80% power to demonstrate 3.5% non-inferiority of IDFS for patients with low Prosigna Score tumors (estimated 65% of participants). Cox proportional hazards models will be used to explore important prognostic factors including menopausal status. Additional secondary endpoints include DRFI. A cost-effectiveness analysis of protocol specified MPA driven treatment against standard clinical practice will be conducted. At 31/01/2021, 2004 patients had been randomized. The DMC reviewed the trial in December 2020 with knowledge of related trial results and suggested that the trial continues as planned.