Everolimus: Targeted Therapy on the Horizon for the Treatment of Breast Cancer

The mammalian target of rapamycin ( mTOR ) is a signaling kinase of the phosphatidylinositol 3‐kinase/protein kinase B (also known as Akt) signaling pathway that mediates cell growth and metabolism. Dysregulation of the mTOR pathway creates a favorable environment for the development and progression of many cancers, including breast cancer, and is associated with the development of resistance to endocrine therapy and to the anti–human epidermal growth factor receptor‐2 (HER2) monoclonal antibody trastuzumab. Therefore, the addition of mTOR inhibitors to conventional breast cancer therapy has the potential to enhance therapeutic efficacy and/or overcome innate or acquired resistance. Everolimus, an mTOR inhibitor with demonstrated preclinical activity against breast cancer cell lines, has been shown to reverse Akt ‐induced resistance to hormonal therapy and trastuzumab. Phase I–II clinical trials have demonstrated that everolimus has promising clinical activity in women with HER2 ‐positive, HER2 ‐negative, and estrogen receptor–positive breast cancer when combined with HER2 ‐targeted therapy, cytotoxic chemotherapy, and hormonal therapy, respectively. Everolimus is generally well tolerated; hematologic abnormalities and stomatitis are most common adverse events when this drug is combined with cytotoxic chemotherapy. Based on these promising results, everolimus is currently under evaluation in a series of phase III Breast Cancer Trials of Oral Everolimus ( BOLERO ) trials of women with HER2 ‐positive and estrogen receptor–positive breast cancer. Results of these trials will help to establish the role of everolimus in the treatment of clinically important breast cancer subtypes.