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Published on 2 November 2009

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New long-term studies support exemestane use in post-menopausal women with breast cancer

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Aromasin offers prolonged protection following 2-3 year tamoxifen therapy

Steve Dawber
Freelance medical writer

New long-term data[1] presented last month at the Joint ECCO 15th-34th ESMO Multidisciplinary Congress in Berlin have revealed that post-menopausal women with early breast cancer who have been taking tamoxifen therapy for 2-3 years, have a lower risk of death and are more likely to remain cancer free if their treatment is switched to exemestane (Aromasin).

Charles Coombes, (clinical professor, division of surgery, Imperial College, London, UK and leader of this Intergroup Exemestane Study (IES)) said: “We had already demonstrated that switching adjuvant therapy to exemestane after 2-3 years tamoxifen therapy could evoke disease-outcome benefits in postmenopausal patients with early breast cancer. However, until now, the magnitude and duration of the overall survival benefit had been uncertain. The aim of our latest analysis is to update the survival and efficacy data when at least 90% of the study patients had been followed-up for at least six years.”

During the double-blind study, 4,724 patients from 37 countries received tamoxifen therapy for an initial period of 2-3 years. All patients had oestrogen-receptor- positive (ER+) or ER-unknown receptor status, had had their tumours resected (cut out), and had remained disease-free throughout their two-to-three years of tamoxifen therapy. After this initial treatment period, patients were randomised to receive either exemestane or tamoxifen for a total of five years. The results after 91-months of follow-up showed that when compared to oestrogen-receptor-positive (ER+) or ER-unknown patients who remained on tamoxifen, ER+ or ER-unknown patients who were switched to exemestane were significantly more likely to have survived (HR=0.86; p=0.04) and significantly less likely to have suffered a disease-free survivalevent (defined as a local or distant recurrence of breast cancer, contralateral breast cancer, or death from any cause; HR=0.82; p=0.0009).

Professor Coombes explained: “These latest findings have confirmed that the strategy of switching to exemestane mid-way through the five-year tamoxifen treatment plan provides a clear and durable benefit for relapse and overall survival. Our updated results show that the relapse improvement does not seem to diminish over time and have clarified that the survival advantage is robust and enduring. Six years after changing treatment, women who received exemestane were 18% more likely to remain disease-free and 14% less likely to die than those who stayed on tamoxifen.

“Exemestane was also associated with a lower number of cardiovascular, musculoskeletal, and gynaecological events, all of which contributed to its significantly superior survival profile. Importantly, serious exemestane-related side effects were rare, and switching from tamoxifen appeared to minimise the adverse risks of both agents.”

Breast cancer is still the most prevalent cancer in women, with 1.3 million cases diagnosed worldwide every year.[2] Around two-thirds of breast cancers are oestrogen-dependent,[3] meaning that oestrogen plays an important role in promoting the growth. Such tumours are usually treated with anti-oestrogen drugs. Tamoxifen, the oldest of these, blocks the tumour’s ability to use oestrogen and is the standard treatment after surgery in women who have early-stage breast cancer. Exemestane belongs to a newer class of anti-oestrogen drugs known as aromatase inhibitors, which interfere with the function of aromatase, an enzyme responsible for the production of oestrogen. Aromatase inhibitors are accepted as an alternative to tamoxifen for post-menopausal women, but the question of how best to use these drugs remains under investigation.

“Practice changed in many countries after our early findings were released in 2004. Instead of using five years of tamoxifen therapy, the current recommended treatment strategy is to switch patients to exemestane or another aromatase inhibitor after two or three years of tamoxifen. The issue that has yet to be clarified however, is whether starting with tamoxifen and then switching is better than starting with an aromatase inhibitor”, concluded Professor Coombes.

TEAM approach shows Aromasin has long-term clinical benefits
Fittingly, the largest worldwide study of treatments for post-menopausal, hormone positive breast cancer has sought to answer this important question. The TEAM (Tamoxifen Exemestane Adjuvant Multinational) Study was designed to compare survival and other disease-related outcomes between patients receiving initial tamoxifen therapy and patients receiving initial exemestane therapy, and the latest 33-month data from the study were presented at the Joint ECCO 15th-34th ESMO Multidisciplinary Congress in Berlin, by Cornelis van de Velde, (professor of Surgery, Leiden University Medical Centre).[4]

The TEAM trial was started in 2001, but in 2004, based on results from the Intergroup Exemestane Study that showed a significant survival advantage for patients on exemestane, the TEAM study was changed so that patients receiving tamoxifen were switched to exemestane after having been in the trial for two-to three years.

Professor van de Velde explained: “Originally, TEAM was designed as a five-year trial that aimed to compare exemestane therapy with tamoxifen therapy. The Global Steering Committee then underlined scientific and clinical reasons to modify the trial design. In addition to a direct exemestane versus tamoxifen comparison at 2.75 years, it was also decided to switch patients on tamoxifen to exemestane, and compare sequential tamoxifen-exemestane therapy with continuous exemestane therapy.”

The randomised phase III clinical trial recruited a total of 9,779 women from nine countries (1,230 from France, 1,480 from Germany, 211 from Greece, 184 from Japan, 2,753 from The Netherlands, 414 from Belgium, 1,275 from the UK and Ireland, and 2,232 from the USA). After 2.75 years of follow-up, when compared to those women receiving tamoxifen, the women who received exemestane experienced 11% fewer cases of a local tumour recurrence, distant metastases, breast cancer of the other breast (contralateral breast cancer), and relapse-free deaths. There were no differences between the two groups in overall survival and no unexpected safety issues were reported.

“This current analysis covers a short period of time when relatively few deaths have occurred, and this makes it difficult to see significant differences between the two groups. However, the data from TEAM indicate that early use of exemestane in these high-risk patients appears to be safe and a more effective endocrine treatment than tamoxifen for reducing breast cancer
recurrence.

“The next study end point has already been reached, and we now have enough events to conclude whether starting with tamoxifen and switching to exemestane is better or worse than starting with exemestane. These results will be presented at the San Antonio Breast Cancer Symposium in December”, concluded Professor van de Velde.

References
1. Coombes RC. Surviva land safety post study treatment completion: an updated analysis of the Intergroup Exemestane Study (IES). Presented at the Joint ECCO 15th–34th ESMO Multidisciplinary Congress, Berlin, Germany, 20th–24th September 2009.
2. ACS – Global Cancer Facts & Figures 2007. Available at: http://www.cancer.org/downloads/ STT/Global_Facts_and_ Figures_2007_rev2.pdf (accessed November 11, 2008).
3. Brueggemeier RW. Overview of the pharmacology of the
aromatase inactivator exemestane. Breast Cancer Res Treat. 2002 July:74(2):177–85.
4. van de Velde CJH. Results of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized
phase III trial in hormone sensitive postmenopausal early breast cancer. Presented at the Joint ECCO 15th-34th ESMO Multidisciplinary Congress, Berlin, Germany, 20th-24th September 2009.



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