Adjuvant tamoxifen and exemestane in early breast cancer (TEAM)
April, 2011
Commentary by Dr Richard de Boer
Van de Velde CJH, Rea D, Seynaeve C et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 2011;377:321-31
The reviewer
Dr Richard de Boer is Consultant Medical Oncologist at the Royal Melbourne, Epworth-Freemasons and Western Hospitals, Melbourne.
SUMMARY
Abbreviations
Aromatase Inhibitor (AI); Confidence Interval (CI); Disease-Free Survival (DFS); Overall Survival (OS); Relapse-Free Survival (RFS); Tamoxifen Exemestane Adjuvant Multinational (TEAM)
Study Design
The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial is a large randomised controlled trial comparing exemestane alone for 5 years, to tamoxifen for 2.5–3 years followed by exemestane to complete a total of 5 years of endocrine therapy, see Figure 1. The trial included 9779 postmenopausal women (median age 64 years, range 35 – 96) with hormone-receptor-positive breast cancer. The primary endpoint was disease-free survival (DFS); secondary endpoints were overall survival (OS), relapse-free survival (RFS) and safety. Median follow-up was 5.1 years.
Findings
Similar rates for DFS and OS at 5 years were observed in both groups, see Table 1. Subgroup analysis by characteristics such as grade, stage, progesterone-receptor status, treatment and age did not identify any patients as benefiting more from either strategy. There was no significant difference in the cumulative incidence of relapse between the sequential treatment group and the exemestane alone group (p=0.29).
The following adverse events were reported more often in the sequential treatment group: gynaecological symptoms, postmenopausal bleeding, endometrial abnormalities and venous thrombosis. Exemestane alone was associated with higher rates of musculoskeletal adverse events, osteoporosis and fractures, and with higher incidence of hypertension, hyperlipidaemia and cardiac failure.
Table 1
| Outcome |
Tamoxifen followed by exemestane |
Exemestane alone |
Hazard ratio (95% CI) |
|
5 yr disease-free survival (intention-to-treat) |
85% |
86% |
0.97 (0.88 to 1.08) p=0.6 |
|
5 yr disease-free survival (per protocol) |
86% |
87% |
0.93 (0.82 to 1.05) p=0.22 |
|
5 yr overall survival |
91% | 91% |
1.00 (0.89 to 1.14) p>0.99 |
Conclusion
The authors concluded that exemestane alone or tamoxifen followed by exemestane may be appropriate options for treating postmenopausal women with hormone-receptor-positive early breast cancer.
COMMENTARY
What does this article add to existing clinical evidence in this area?
Results from the adjuvant aromatase inhibitor (AI) trials (e.g. ATAC, BIG 1-98, and IES) have changed clinical practice. Guidelines now recommend the addition of an AI at some point in the adjuvant endocrine management of postmenopausal women with hormone-positive early breast cancer.1 Nevertheless, the best strategy: upfront 5 years of AI, switch from tamoxifen to AI at 2-3 years, or extended AI after 5 years, remains unknown. The BIG 1-98 trial with its four arms, comparing 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other, found little difference between letrozole monotherapy and sequential treatments,2 except perhaps in higher risk patients.
The TEAM study directly compared exemestane monotherapy and sequential treatment (tamoxifen followed by exemestane) and found no difference in either DFS or OS at 5 years.3 This confirms the overall results of the BIG 1-98 trial. It is interesting to note that there was a large minority of higher risk patients in the TEAM trial with 41% having tumours over 2cm, 42% being node positive and 25% having high grade tumours. In addition, 64% received no adjuvant chemotherapy. Despite this there were excellent overall outcomes for the study group; 5 year OS rate of 91%, and a DFS rate of 86%. Hence, this trial emphasizes the primary importance of endocrine therapy in this patient population, and the excellent results that can be achieved in patients with endocrine therapy alone. Subgroup analysis did not show greater efficacy in higher risk patients for treatment with 5 years of exemestane. Toxicity profiles between the two arms were different. Not surprisingly, the sequential arm saw more endometrial, gynaecological and thrombotic events (due to the oestrogenic effect of tamoxifen), whilst the 5 years of AI resulted in more osteoporosis, fractures and cardiac events, confirming data from earlier trials.
How adequate was the methodology used in addressing the aim of this study?
The trial was large, well conducted and the methodology used appears appropriate and adequate. The structure of the trial was changed once the results of the IES trial came through,4 but this does not appear to have impacted on the final results. One concern is the number of patients who failed to complete the 5 years of treatment (56% in the sequential arm and 30% in the exemestane arm). Also, 22% of patients commencing tamoxifen stopped before completing their 2-3 years of the drug. It is unclear if these patients went on to alternative endocrine therapy, or stopped altogether. If the latter occurred, then the result in the sequential arm is even more impressive.
What are the implications of this study for clinical practice in Australia?
This study has important implications for clinical practice in Australia. It adds to the growing evidence that tamoxifen still has an important role to play in patients who are postmenopausal. Clearly upfront AI for 5 years is a good option, but it is not the only option. The sequential strategy appears just as effective in all patient subpopulations. This gives the treating physician the confidence to employ either strategy, with perhaps the toxicity profile and patient preferences playing a larger role in guiding recommendations. Clearly, pre-existing bone and cardiovascular morbidities need to be considered before starting with an upfront AI. Although exemestane is the least commonly used AI in Australia, the recently reported MA.27 study5 showed equal efficacy between 5 years of exemestane and 5 years of anastrozole. Thus, it would seem reasonable to extrapolate the TEAM trial results to the use of anastrozole.
References
1. National Breast Cancer Centre**. Recommendations for aromatase inhibitors as adjuvant endocrine therapy for post-menopausal women with hormone receptor-positive early breast cancer. Camperdown: National Breast Cancer Centre**; 2006.
2. The BIG 1-98 Collaborative Group. Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer. N Engl J Med 2009;361:766-76.
3. Van de Velde CJH, Rea D, Seynaeve C et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 2011;377:321-31.
4. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-92.
5. Goss PE, Ingle JN, Chapman J-AW, et al. Final Analysis of NCIC CTG MA.27: A Randomized Phase III Trial of Exemestane Versus Anastrozole in Postmenopausal Women with Hormone Receptor Positive Primary Breast Cancer. San Antonio Breast Cancer Symposium. 2010;Abstract;S1-1.
Editor: Dr Anne Nelson, Evidence Review and Research Leader, National Breast and Ovarian Cancer Centre*
Clinical Update – Breast Cancer Editorial Committee: Mr John Collins - Surgeon, Ms Jo Keyser - Specialist Breast Nurse, Dr Warwick Lee - Radiologist, A/Prof Liz Lobb – Senior Research Fellow, Dr Sue-Anne McLachlan - Medical Oncologist, Dr Sally Meade - Breast Surgeon, Dr Sue Pendlebury - Radiation Oncologist, A/Prof Martin Stockler - Medical Oncologist.
Disclaimer
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** In February 2008, National Breast Cancer Centre (NBCC), incorporating the Ovarian Cancer Program, changed its name to National Breast and Ovarian Cancer Centre (NBOCC). In July 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia, to provide leadership in cancer control and improve outcomes for Australians affected by cancer.