Managing postmenopausal women with hormone receptor-positive advanced breast cancer who progress on endocrine therapies with inhibitors of the PI3K pathway

Abstract

Although endocrine therapies that interfere with estrogen receptor (ER)-mediated signaling have revolutionized the management of postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), long-term management of these patients is suboptimal because of the eventual emergence of endocrine resistance. Intense research has elucidated a number of targets that act downstream or upstream of the ER, as well as those that crosstalk with the ER; however, clinical validation of inhibiting specific targets to overcome endocrine resistance has been lacking. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated to mediate endocrine resistance, and a number of novel agents that target this pathway are in early- and late-stage clinical trials. Recently, everolimus, an inhibitor of mTOR, a critical component of the PI3K/AKT/mTOR pathway, in combination with endocrine therapy, was shown to prolong progression-free survival with a manageable adverse-event profile in postmenopausal patients with HR+ BC. Bolstered by the safety and efficacy observed with concomitant inhibition of the ER and the PI3K/mTOR pathway and the validation of dual inhibition approach in managing postmenopausal patients with HR+ BC, a number of novel agents that inhibit PI3K (pan-PI3K inhibitors) or PI3K and mTOR (dual PI3K/mTOR) are being evaluated in clinical trials. Thus, mTOR inhibitors have provided the much-needed ammunition to oncologists who manage postmenopausal women with BC and have paved the way for the development of novel therapies that target the PI3K/mTOR pathway. Use of these novel therapies in managing postmenopausal women with BC, in combination with endocrine therapies, is expected to improve overall outcomes by overcoming endocrine resistance.

Keywords: PI3K pathway; endocrine resistance; mTOR inhibitor.