In a study of circulating tumor DNA (ctDNA) genomic profiles in advanced breast cancer, it has been demonstrated that subclonal mutations in HR-positive and HER2-negative breast cancers were enriched for APOBEC signatures and are continuously activated during endocrine therapy to modify PIK3CA (Law et al., 2016), generating frequent secondary hits of new mutations that upregulate PI3K signaling (Kingston et al., 2021). The gene discussed is PIK3CA; the disease is breast cancer.