Everolimus: targeted therapy on the horizon for the treatment of breast cancer

• Published in: Pharmacotherapy Vol. 32; no. 4; p. 383
• Main Author: Barnett, Chad M
• Format: Journal Article
• Language: English
• Published: United States 01.04.2012
• Subjects: Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Interactions; Everolimus; Female; Humans; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Receptor, ErbB-2 - genetics; Receptors, Estrogen - genetics; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 1875-9114
• DOI: 10.1002/j.1875-9114.2012.01084.x

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.