Elsevier

The Lancet

Volume 359, Issue 9324, 22 June 2002, Pages 2131-2139
The Lancet

Fast track — Articles
Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial*

https://doi.org/10.1016/S0140-6736(02)09088-8Get rights and content

Summary

Background

In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side-effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years.

Methods

Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. The primary endpoints were disease-free survival and occurrence of adverse events. Analysis for efficacy was by intention to treat.

Findings

9366 patients were recruited, of whom 3125 were randomly assigned anastrozole, 3116 tamoxifen, and 3125 combination. Median follow-up was 33·3 months. 7839 (84%) patients were known to be hormone-receptor-positive. Diseasefree survival at 3 years was 89·4% on anastrozole and 87·4% on tamoxifen (hazard ratio 0·83 [95% CI 0·71–0·96], p=0·013). Results with the combination were not significantly different from those with tamoxifen alone (87·2%, 1·02 [0·89–1·18], p=0·8). The improvement in disease-free survival with anastrozole was seen in the subgroup of hormonereceptor-positive patients, but not the receptor-negative patients. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio 0·42 [0·22–0·79], p=0·007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer (p=0·02), vaginal bleeding and discharge (p<0·0001 for both), cerebrovascular events (p=0·0006), venous thromboembolic events (p=0·0006), and hot flushes (p<0·0001). Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (p<0·0001 for both).

Interpretation

Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Longer follow-up is required before a final benefit:risk assessment can be made.

Introduction

Many breast cancers depend on oestrogens for their continued growth. Depriving the tumour of this stimulus is an established method of treating the disease.1, 2 In the adjuvant setting, tamoxifen is the established treatment for women with hormone-sensitive disease. This drug has substantial benefits in terms of disease-free and overall survival, and can reduce rates of contralateral breast cancer compared with control or placebo.3, 4 Furthermore, the continuing Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overviews have provided definitive confirmation of the value of tamoxifen. The most recently published analysis showed that, in patients with hormone-receptor-positive disease, the odds of recurrence and death were reduced by 47% and 26%, respectively, after about 5 years of treatment.5

In addition to its established antitumour efficacy, tamoxifen therapy provides other beneficial effects—eg, protection against bone loss in postmenopausal women6— that relate to the partial oestrogen-agonist action of the drug. However, these partial agonist effects are also associated with several clearly defined risks. Although tamoxifen is generally well tolerated, lengthy use of this agent is associated with gynaecological complications, including proliferative endometrial abnormalities in postmenopausal women. An increased incidence of endometrial cancer has been reported in association with tamoxifen treatment, and the level of risk seems to be time-dependent and dose-dependent.7 Many studies have found a two to four times higher relative risk of developing endometrial cancer in women taking tamoxifen than in an age-matched population.5, 8 Most cases of endometrial cancer after tamoxifen treatment are low-grade stage 1 tumours,9 but a small proportion are high-grade sarcomas.10 Other side-effects related to the oestrogenic properties of tamoxifen include an increased risk of thromboembolic disorders, especially when given in combination with chemotherapy.11, 12

In the mid-1990s, the third-generation aromatase inhibitors became available, initially for the treatment of advanced breast cancer in postmenopausal women for whom tamoxifen therapy fails. Aromatase inhibitors are a class of compounds that inhibit the synthesis of oestrogen from androgens in postmenopausal women. Anastrozole (Arimidex), which became available in 1995, is a potent, orally active, highly selective, non-steroidal aromatase inhibitor that substantially reduces oestrogen concentrations in postmenopausal women with breast cancer.13

In advanced disease, anastrozole is well tolerated and has a significant survival advantage over megestrol acetate as second-line treatment.14 It was also shown to be better than tamoxifen with respect to time to progression when used as first-line treatment for advanced breast cancer in a North American trial,15 and to be at least as effective as tamoxifen with respect to time to progression in a second, larger international trial.16 A combined analysis of the two trials showed anastrozole to be at least as good as tamoxifen in the overall population, and to result in a significantly increased time to progression compared with tamoxifen in patients with known hormone-receptorpositive disease.17 Additionally, anastrozole led to reduced incidences of thromboembolic disease and vaginal bleeding in these studies.

Thus, the place of tamoxifen as the gold standard for the first-line treatment of postmenopausal women with advanced hormone-sensitive breast cancer has recently been challenged by anastrozole. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial compared the established adjuvant treatment, tamoxifen, with anastrozole alone and in combination with tamoxifen as adjuvant treatment for postmenopausal women with early, operable breast cancer. The trial was designed to answer the following questions: (1) Is anastrozole at least as effective as tamoxifen in postmenopausal women with early operable breast cancer? (2) Does anastrozole offer any safety or side-effect benefits over tamoxifen in this group of patients? (3) Could a combination of anastrozole plus tamoxifen offer additional efficacy or safety benefits over tamoxifen alone? Inclusion of a combination group allowed investigation of any possible additive effects through the use of two drugs with different modes of action. Here we report the first efficacy and safety results of the ATAC trial.

Section snippets

Patients

Eligible patients were postmenopausal women with histologically proven operable invasive breast cancer who had completed primary surgery and chemotherapy (where given), and were candidates to receive hormonal adjuvant therapy. Patients were defined as being postmenopausal if they satisfied one or more of the following criteria: having had a bilateral oophorectomy; aged more than 60 years; or aged 45–59 years with an intact uterus and amenorrhoeic for at least 12 months. If a patient had been

Patients

9366 women from 381 centres in 21 countries were enrolled between July 12, 1996, and March 24, 2000 (figure 1). Of these women, 125 were found to be ineligible after randomisation (70 were too young or not postmenopausal; 25 had previous cancer; 20 had taken a non-approved drug in the previous 3 months; the rest for a variety of reasons). The results presented below include all randomised patients analysed on an intention-to-treat basis. 5695 (61%) patients were lymph-node negative, 5959 (64%)

Discussion

Endocrine therapy for breast cancer has enjoyed a renaissance since the introduction of tamoxifen in the 1970s. Indeed, we can now be confident that, for hormonereceptor-positive patients, both premenopausal and postmenopausal, about 5 years of tamoxifen treatment is associated with a 47% reduction in disease recurrence rates and a 26% reduction in overall mortality.5

Although relatively well tolerated, about 30% of women on tamoxifen complain of hot flushes, vaginal discharge, or vaginal

References (28)

  • Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer

    J Natl Cancer Inst

    (1996)
  • Tamoxifen for early breast cancer: an overview of the randomised trials

    Lancet

    (1998)
  • RR Love et al.

    Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years

    Arch Intern Med

    (1994)
  • Tamoxifen and endometrial cancer

    Obstet Gynecol

    (2000)
  • Cited by (1912)

    View all citing articles on Scopus
    *

    Members listed at end of paper

    View full text