Elsevier

The Lancet Oncology

Volume 11, Issue 12, December 2010, Pages 1135-1141
The Lancet Oncology

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Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial

https://doi.org/10.1016/S1470-2045(10)70257-6Get rights and content

Summary

Background

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months.

Methods

We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230.

Findings

Patients were followed up for a median of 120 months (range 0–145); there were 24 522 woman-years of follow-up in the anastrozole group and 23 950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 0·91, 95% CI 0·83–0·99; p=0·04), time to recurrence (0·84, 0·75–0·93; p=0·001), and time to distant recurrence (0·87, 0·77–0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78–0·95; p=0·003), time to recurrence (0·79, 0·70–0·89; p=0·0002), and time to distant recurrence (0·85, 0·73–0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67–0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74–1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84–1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15–1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74–1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48–0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60–1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported.

Interpretation

These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

Funding

AstraZeneca.

Introduction

Previous reports from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial1, 2, 3 have shown significantly prolonged disease-free survival, lower rates of recurrence and distant recurrence, and significantly reduced contralateral breast cancer in patients treated with anastrozole compared with tamoxifen. Additionally, anastrozole was associated with significantly fewer serious adverse events than tamoxifen, including fewer patients with endometrial cancer, but increased numbers of fractures and reports of arthralgia during treatment.4 Dowsett and colleagues5 have summarised the role of aromatase inhibitors, such as anastrozole, in the adjuvant treatment of early breast cancer.

A 10-year median follow-up of the ATAC trial was completed to satisfy a US Food and Drug Administration requirement for updated efficacy and safety information. This analysis provided about 13 months of additional follow-up data beyond the previously published 100-month follow-up report,3 but only assessed disease-free survival, time to recurrence, overall survival, and safety for all patients. Here, we extend this analysis to include also time to distant recurrence and incidence of contralateral breast cancer, and report the updated data from the ATAC trial at 120 months follow-up.

Section snippets

Patients and procedures

The ATAC trial has been described in detail previously.6 Briefly, eligible patients were postmenopausal women with histologically proven operable invasive breast cancer. Patients were randomly assigned (1:1:1) to receive active anastrozole plus tamoxifen placebo, active tamoxifen plus anastrozole placebo, or active anastrozole plus active tamoxifen. Anastrozole was given as 1 mg and tamoxifen as 20 mg daily oral tablets for 5 years. The combination treatment group was discontinued after the

Results

Median follow-up for this analysis was 120 months (range 0–145). This follow-up included a total of 48 473 women-years of follow-up (24 522 woman-years for anastrozole and 23 950 woman-years for tamoxifen). Baseline characteristics have been described previously;6 the median age at this analysis was 72 years (IQR 65–91).

Table 1 summarises the results for all efficacy endpoints for all randomised patients and the hormone-receptor-positive subgroup. Overall, hazard ratios were similar to those in

Discussion

This 10-year analysis of the ATAC trial confirms the previously reported efficacy and tolerability benefits of anastrozole as initial adjuvant therapy for postmenopausal women with early hormone-receptor-positive breast cancer (panel; table 4). Tamoxifen has shown a carryover benefit for recurrence in the first 5 years after treatment, but not after that.9 This so-called carryover effect for recurrence was larger for anastrozole than for tamoxifen in the present study and remained significant

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