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). This evidence concerns the gene ERBB2 and breast cancer.