An analysis of the phase III PALOMA-3 study by O'Leary et al. [237, 238], comparing the combination of Fulvestrant + Palbociclib vs Fulvestrant + Placebo, 14 patients underwent paired ctDNA exome analysis showing biological signs of clonal evolution in 85% of cases with new emerging mutations both in all cohorts (PIK3CA, ESR1) or only in the Palbociclib combination arm (RB1) emphasizing a subclonal complexity of hormone-responsive breast cancer. This evidence concerns the gene ESR1 and breast carcinoma.