To illustrate the adoption of different mitigating strategies in study design and conduct, we use the paradigm of IMPORTANT trial that is dedicated to older patients with advanced hormone-receptor (HR)-positive/HER2-negative breast cancer planned to be treated with cyclin-dependent kinase 4/6 (CDK4/6) -inhibitors and endocrine therapy in the first-line setting. Here, NR4A1 is linked to breast cancer.