Evolved ESR1 mutant clones show an initial marked decrease in abundance to both the combination of palbociclib and fulvestrant and fulvestrant alone as assessed by early circulating tumor DNA dynamics, but this does not associate with long-term improvement in PFS on fulvestrant alone relative to patients with wild-type ESR1. ESR1 mutations were more frequently undetectable at the end of treatment than PIK3CA mutations, and early clonal selection of ESR1 mutations can be detected after 15 days treatment, anticipating clonal architecture at progression. This evidence concerns the gene PIK3CA and neoplasm.