Major finding: Everolimus with exemestane improves progression-free survival in breast cancer.
Approach: A phase III trial compared everolimus and exemestane treatment with exemestane alone.
Impact: mTOR inhibition combined with endocrine therapy may improve outcome in breast cancer.
First-line endocrine therapy for postmenopausal patients with hormone -receptor (HR)–positive breast cancer includes treatment with the nonsteroidal aromatase inhibitors letrozole and anastrozole, which block the synthesis of estrogen. However, not all patients respond to first-line endocrine therapy, and even those who do respond eventually develop acquired resistance and progressive disease. Hormone resistance has been linked to activation of the phosphoinositide 3-kinase/AKT/mTOR signaling pathway, which is involved in cell growth and proliferation. In the randomized phase III trial Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2), Baselga and colleagues demonstrate that combination treatment with everolimus, an mTOR inhibitor traditionally used as an immunosuppressant, and the steroidal aromatase inhibitor exemestane dramatically improves progression-free survival in patients with metastatic HR-positive breast cancer. A total of 724 postmenopausal women with advanced HR-positive breast cancer, all of whom had failed treatment with nonsteroidal aromatase inhibitors, were randomized to receive a combination of everolimus and exemestane or exemestane and placebo. Significantly, median progression-free survival increased from 4.1 months to 10.6 months in the everolimus combination group compared with the exemestane and placebo group. Adverse events, including oral ulcers, anemia, shortness of breath, and fatigue, were also increased in the combination-therapy group. Although additional follow-up is required to evaluate whether the addition of everolimus will lead to an overall survival benefit, these findings represent a major advance in the treatment of advanced HR-positive breast cancer, especially for patients whose disease continues to progress despite sequential treatment with multiple endocrine therapies. Studies with everolimus and hormonal agents are currently being planned for earlier stages of breast cancer.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.
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