Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomized phase III trial
Study Design: Phase III, multinational randomized controlled trial. Women were randomly assigned in a 1:1 ratio to open-label exemestane alone or following tamoxifen (sequential treatment) for 5 years with disease-free survival as a primary endpoint.
Study Eligibility: Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer. Other inclusion criteria included invasive tumors of all sizes, with or without lymph node involvement (N0 to N3) and no evidence of metastatic disease.
Enrollment: 9,766 patients in the intention-to-treat population – 4,868 patients assigned to sequential treatment and 4,898 assigned to exemestane alone
Research Question: Are exemestane monotherapy and tamoxifen followed by exemestane for 5 years equally effective in improving disease-free survival in hormone-receptor positive, postmenopausal breast cancer?
It is unclear whether differences exist between aromatase inhibitor monotherapy and sequential therapy strategies for hormone-receptor positive, postmenopausal breast cancers. In the meantime, many doctors generally prescribe adjuvant treatment with an aromatase inhibitor alone for 5 years. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial is a phase III, an open-label randomized controlled trial that was originally designed to compare exemestane with tamoxifen in postmenopausal women with hormone-receptor-positive, early breast cancer. After results from the Intergroup Exemestane Study demonstrated that patients who switched to exemestane after 2-3 years of tamoxifen had significantly better disease-free survival versus those continuing tamoxifen, the TEAM protocol was amended to compare monotherapy and sequential therapy strategies. In this analysis, the researchers compared exemestane alone with tamoxifen followed by exemestane for 5 years for disease-free survival (DFS).
The TEAM trial was conducted in 566 hospitals in Belgium, France, Germany, Greece, Japan, the Netherlands, the UK and Ireland, and the US. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane alone (25 mg once a day, orally) or exemestane following 2.5-3 years of tamoxifen (20 mg once a day, orally) for 5 years with DFS as the primary endpoint. Secondary endpoints were overall survival, relapse-free survival, and safety. Patients with invasive tumors of all sizes, with or without lymph node involvement (N0 to N3) and no evidence of metastatic disease were included. Exclusion criteria included substantial cardiac disease, other malignant diseases, or illnesses interfering with participation in the study. Patients began treatment within 10 weeks of completion of definitive surgery and chemotherapy if indicated.
The median follow-up was 5.1 years and 60% of patients completed at least 5 years of follow-up. A total of 9,766 patients comprised the “intention-to-treat” population used in this analysis. Of these women, 4,868 were randomized to receive exemestane after 2-3 years of tamoxifen (sequential treatment) and 4,898 were assigned to exemestane alone for 5 years. A total of 4,154 patients in the sequential group and 4,186 in the exemestane group remained disease-free, with no significant difference in 5-year DFS between the two treatment arms (HR=0.97, 95% CI=0.88-1.08). This finding remained true in subgroup analysis stratified by tumor characteristics, treatments received, and patient age. There was also no significant difference between the groups with respect to overall survival, with 91% of patients in both groups alive at the end of follow-up. Moreover, relapse-free survival was similar between the groups.
In the safety analysis, exemestane monotherapy was associated with an increased incidence of osteoporosis and fractures, hypertension, hyperlipidemia, and cardiac failure. On the other hand, sequential treatment was associated with an increased incidence of gynecological symptoms, venous thrombosis, and endometrial abnormalities. These different adverse event profiles may play an important role in treatment decisions for an individual patient and further research is needed to identify specific patient populations that might benefit more from one treatment option over another. However, the results of this study suggest that treatment regimens of exemestane alone or after tamoxifen may both be appropriate options for postmenopausal women with hormone-receptor-positive, early breast cancer.
While this study was adequately powered to detect differences between the treatment arms, this power may have been slightly compromised by high rates of discontinuation or non-compliance, particularly during the tamoxifen period. Results reported during this trial showing the better efficacy of aromatase inhibitors than of tamoxifen may have influenced patients or doctors to switch early to exemestane monotherapy or discontinue treatment. This is one key drawback to open-label studies versus blinded designs.
Van de Velde CJ, Rea D, Seynaeve C, et al. “Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomized phase 3 trial.” Lancet 2011 January 22; 377: 321-331. Select ScienceDirect to view the article.