Notably, in an exploratory analysis of the global BOLERO-2 study, PFS benefit was observed with the combination of everolimus (a mechanistic target of rapamycin [mTOR] inhibitor) and exemestane versus placebo–exemestane in patients with HR-positive/HER-2 negative advanced breast cancer previously treated with non-steroidal aromatase inhibitors (without CDK4/6 inhibitors) and with a normal (not hyperactive) PI3K pathway activity32. This evidence concerns the gene PIK3CA and breast carcinoma.