In another analysis of plasma ctDNA from patients involved in the PALOMA-3 study (n = 195), O’Leary et al. showed that clonal evolution frequently occurs during treatment, reflecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy, and new driver mutations emerged in PIK3CA and ESR1 (in particular, ESR1 Y537S) after treatment with either palbociclib plus fulvestrant or placebo plus fulvestrant [185]. This evidence concerns the gene ESR1 and breast cancer.