Thus, in ER-positive tumors, the high degree of crosstalk between ER and the PI3K/AKT/mTOR pathway could inhibit the response to mTOR inhibitors, as observed in the BOLERO-1 and BOLERO-3 trials [45,46], supporting the double targeting of ER and mTOR, which has been performed in ER-positive HER2-negative BC patients [47]. This evidence concerns the gene ESR1 and breast cancer.