There are several ongoing major randomized trials with everolimus in HR-positive advanced breast cancer including BOLERO-4, which will evaluate the benefit from the combination of everolimus and letrozole as first-line treatment (NCT01698918) and might be able to determine if the lack of benefit observed with temsirolimus in the HORIZON study was related to patient population, as preclinical studies have observed that the PI3K/Akt/mTOR pathway is mostly activated after previous endocrine therapy exposure. This evidence concerns the gene AKT1 and breast carcinoma.