Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial

The development of the 70-gene prognosis signature for breast cancer was evaluated in the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial to assess the clinical relevance of the 70-gene prognosis signature, and how this compares with traditional prognostic factors for assigning adjuvant chemotherapy for patients with node-negative breast cancer. This review outlines the background work and rationale behind the final design of the MINDACT trial and how these considerations can help to optimize future trials and aim to improve individualization of cancer therapy. This Review describes the work conducted by the TRANSBIG consortium in the development of the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial. The goal of the trial is to provide definitive evidence regarding the clinical relevance of the 70-gene prognosis signature, and to assess the performance of this signature compared with that of traditional prognostic indicators for assigning adjuvant chemotherapy to patients with node-negative breast cancer. We outline the background work and the key questions in node-negative early-stage breast cancer, and then focus on the MINDACT trial design and statistical considerations. The challenges inherent in this trial in terms of logistics, implementation and interpretation of the results are also discussed. We hope that this article will trigger further discussion about the difficulties of setting up and analyzing trials aimed at establishing the worth of new methods for better selection of patients for cancer treatment. Key Points In the past 20 years, little progress has been made regarding new prognostic markers that can assist oncologists in treatment decision-making for node-negative early-stage breast cancer By using gene-expression profiling, the Netherlands Cancer Institute developed a 70-gene prognostic signature for node-negative breast cancer that has now been commercialized. This signature was developed as a dichotomous risk classification for the endpoint of distant metastasis within 5 years and has been retrospectively validated in two series of patients The MINDACT clinical trial will prospectively validate the 70-gene prognostic signature Validation of the risk of distant relapse will be assessed through clinicopathologic criteria, using Adjuvant! Online and MammaPrint ® (Agendia). In case of discordant results, patients will be randomized to treatment decision-making based on clinicopatholog