Everolimus in hormone receptor-positive advanced breast cancer: targeting receptor-based mechanisms of resistance.

Although patients with hormone receptor (HR)-positive breast cancer are successfully treated with endocrine therapy, many tumors go on to develop resistance to these agents. Studies have determined that mechanisms of resistance to endocrine therapy are quite complex and can involve a multitude of signal transduction pathways, either through direct association with the estrogen receptor or through cross-talk with other pathways. Preclinical studies have suggested the therapeutic importance of the mammalian target of rapamycin (mTOR) pathway and that inhibiting this pathway may restore sensitivity to endocrine therapy. The oral mTOR inhibitor everolimus has been extensively studied for breast cancer. Clinical studies suggest that everolimus in combination with endocrine therapy improves progression-free survival and is well tolerated. A combined approach, targeting both mTOR signal transduction and the HR pathways, promises to take clinical research in a new direction for the treatment of HR-positive advanced breast cancer.