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Chicago, IL—Several sub-analyses of the international randomized phase 3 Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2)1 plus exemestane vs exemestane alone for the treatment of postmenopausal women with HER2-negative, hormone receptor-positive (HR+) advanced breast cancer, including updated efficacy results,2 health-related quality of life (QOL),3 effects in Asian populations,4 and safety in women over 65 years of age,5 were explored in presentations here at the 2012 Annual Meeting of the American Society of Clinical Oncology.  


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Endocrine therapy is the mainstay of treatment for patients with HR+ advanced breast cancer; however, de novo or acquired resistance to endocrine therapy can occur. In endocrine-resistant breast cancer cells, hyperactivation of the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway has been observed.6

When the mTOR inhibitor everolimus was examined in preclinical and clinical studies in combination with the nonsteroidal aromatase inhibitor letrozole, a synergistic inhibition of proliferation and apoptosis in breast cancer cells were observed as well as a significantly higher response rate in postmenopausal women with HR+ early breast cancer.7,8 These results suggested mTOR inhibition can enhance efficacy of endocrine therapy, which was an underlying hypothesis for the BOLERO-2 trial.

Results from an interim analysis of BOLERO-2 data at a median follow-up of 12.5 months found that everolimus combined with the steroidal aromatase inhibitor exemestane significantly prolonged progression-free survival (PFS) in patients with HR+ advanced breast cancer previously treated with nonsteroidal aromatase inhibitors.9

The study randomly assigned 724 patients with advanced ER+ breast cancer who had disease recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor (letrozole or anastrozole) in the adjuvant setting or to treat advanced disease (or both) in a 2:1 ratio to everolimus 10mg once daily plus exemestane 25mg once daily or exemestane plus placebo. Patients were excluded if they had HER2-overexpressing tumors, a history of brain metastases, or previous treatment with exemestane or mTOR inhibitors.

The primary end point was PFS by local investigator assessment; secondary end points included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate (ORR).

Baseline disease characteristics, including tumor burden and prior cancer therapy, were well balanced between treatment arms. Median age of the patients was 62 years (range, 34-93 years) in the everolimus plus exemestane arm and 61 years (range, 28-90 years) in the placebo plus exemestane arm; 56% had visceral involvement; and 84% had sensitivity to previous endocrine therapy, defined as response or long stabilization in the metastatic setting or ≥2 years of adjuvant endocrine therapy.

All of the patients had previously received letrozole or anastrozole; 48% had received tamoxifen; and 16%, fulvestrant. A total of 26% of patients had received one chemotherapy regimen for advanced breast cancer; the last therapy before randomization was letrozole or anastrozole in 74% of patients. More than half (53%) had received ≥3 prior therapies.