As an example, we present the progressive evolution of an HR+/HER2− tumor to 100% APOBEC3 exposure over more than 20 years of clinical history and therapeutic pressure of several lines of treatment, including endocrine therapies, CDK4/6i, and PI3K-pathway inhibitors (paired samples from MSK-BR-WGS-03; Extended Data Fig. 3g). Here, CDK4 is linked to neoplasm.