Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis

Summary

Background

For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2–3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years.

Methods

We did a meta-analysis of three clinical trials—the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies—in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2–3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy.

Findings

Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratiro 0·59 [95% CI 0·48–0·74]; p<0·0001), event-free survival (0·55 [0·42–0·71]; p<0·0001), distant recurrence-free survival (0·61 [0·45–0·83]; p=0·002), and overall survival (0·71 [0·52–0·98]; p=0·04).

Interpretation

Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2–3 years to anastrozole.

Introduction

Every year, more than 1 million women worldwide are diagnosed with breast cancer, a disease that accounts for almost a quarter of all female cancers.¹ The highest incidence of breast cancer is in developed countries, with more than 360 000 new cases a year in Europe, and more than 200 000 new cases a year in the USA.¹ Although the worldwide incidence of breast cancer continues to rise, perhaps partly as a result of improved screening programmes, mortality rates are beginning to fall because of earlier detection and advances in treatment. At present, 5-year overall survival for women diagnosed with breast cancer is around 75%.¹

For women with early-stage breast cancer, treatment usually begins with surgery (either breast-conserving lumpectomy or mastectomy), with or without radiotherapy or chemotherapy. In women whose tumours are identified as hormone-positive on examination, these initial interventions targeted at removing or destroying the cancerous tissue are often followed by a course of hormone therapy. For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. Randomised controlled studies show that patients taking tamoxifen for 5 years have better outcomes than those who take tamoxifen for 2 years.2, 3 However, many of these patients will still develop and die from metastatic disease within 5 years of their initial diagnosis. But the duration of adjuvant tamoxifen treatment remains in question. Despite its many benefits, it has been associated with various side-effects, including an increased risk of endometrial cancer and thromboembolic events,4, 5, 6 and resistance to tamoxifen is known to develop in 12–18 months in some patients.⁷

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial,⁸ showed that initial adjuvant treatment of postmenopausal women with early-stage breast cancer with the third-generation aromatase inhibitor anastrozole was more efficacious with a better safety profile than tamoxifen. In addition, several studies9, 10, 11 have shown the benefits of switching to anastrozole compared with remaining on tamoxifen for 5 years. The results of the combined analysis¹¹ of the Arimidex-Nolvadex (ARNO 95) and Austrian Breast and Colorectal Cancer Study Group (ABCSG 8) trials showed that switching postmenopausal women with hormone-sensitive early-stage breast cancer from tamoxifen to anastrozole after 2 years' adjuvant treatment results in a significant improvement in event-free survival compared with those who continued tamoxifen. Results from the original and updated analyses of the Italian Tamoxifen Arimidex (ITA) trial in node-positive women only9, 10 also showed significant clinical benefits from switching to anastrozole after 2–3 years of adjuvant tamoxifen.

Clearly, third-generation aromatase inhibitors have a key role in management of postmenopausal women with early-stage breast cancer, and in 2004, the American Society of Clinical Oncology (ASCO) Technology Assessment recommended that 5 years of tamoxifen alone was no longer the best adjuvant treatment for hormone-sensitive early-stage breast cancer, and that treatment should include use of an aromatase inhibitor to reduce the risk of tumour recurrence.¹² The ASCO assessment favours using the aromatase inhibitor that has been most studied in the setting closest to the individual patient's clinical circumstance.

To increase power and precision, and to help avoid bias or random error, we aimed to do a meta-analysis to compare the effect of switching postmenopausal women with hormone-sensitive early-stage breast cancer to anastrozole after 2–3 years of tamoxifen with being treated with tamoxifen for 5 years.