Understanding the mechanisms linking estrogen receptor (ER) and the PI3K pathway has paved the way for combination treatment using fulvestrant (ER antagonist) and alpelisib, which shows synergistic antitumor activity in patients with PIK3CA-mutated, ER-positive, HER2-negative, advanced breast cancer unresponsive to previous estrogen therapy [9]. This evidence concerns the gene ESR1 and breast cancer.