For example, a trial could evaluate endocrine therapy alone in patients with HR+/HER2- advanced breast cancer with a high score of the ctDNA-based Luminal A signature, and then add CDK4/6 inhibition when the ctDNA-based Luminal B signature increases during therapy versus initiating endocrine therapy and CDK4/6 inhibition upfront. The gene discussed is ERBB2; the disease is breast cancer.