Elsevier

The Lancet

Volume 360, Issue 9336, 14 September 2002, Pages 817-824
The Lancet

Articles
First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial*

https://doi.org/10.1016/S0140-6736(02)09962-2Get rights and content

Summary

Background

Three clinical trials on the use of tamoxifen to prevent breast cancer have reported mixed results. The overall evidence supports a reduction in the risk of breast cancer, but whether this benefit outweighs the risks and side-effects associated with tamoxifen is unclear.

Methods

We undertook a double-blind placebo-controlled randomised trial of tamoxifen, 20 mg/day for 5 years, in 7152 women aged 35–70 years, who were at increased risk of breast cancer. The primary outcome measure was the frequency of breast cancer (including ductal carcinoma in situ). Analyses were by intention to treat after exclusion of 13 women found to have breast cancer at baseline mammography.

Findings

After median follow-up of 50 months (IQR 32–67), 69 breast cancers had been diagnosed in 3578 women in the tamoxifen group and 101 in 3566 in the placebo group (risk reduction 32% [95% Cl 8–50]; p=0·013). Age, degree of risk, and use of hormone-replacement therapy did not affect the reduction. Endometrial cancer was non-significantly increased (11 vs 5; p=0·2) and thromboembolic events were significantly increased with tamoxifen (43 vs 17; odds ratio 2·5 [1.5–4·4], p=0·001), particularly after surgery. There was a significant excess of deaths from all causes in the tamoxifen group (25 vs 11, p=0·028).

Interpretation

Prophylactic tamoxifen reduces the risk of breast cancer by about a third. Temporary cessation of tamoxifen should be considered and the use of appropriate antithrombotic measures is recommended during and after major surgery or periods of immobilisation. Prophylactic use of tamoxifen is contraindicated in women at high risk of thromboembolic disease. The combined evidence indicates that mortality from non-breast-cancer causes is not increased by tamoxifen. The overall risk to benefit ratio for the use of tamoxifen in prevention is still unclear, and continued follow-up of the current trials is essential.

Introduction

The belief that oestrogen is the primary promotional factor for breast cancer has a long history and is now well established.1, 2, 3, 4 Attempts to control the incidence of breast cancer by decreasing the oestrogenic stimulus are more recent. The marked reduction in the rate of new contralateral tumours found when tamoxifen was used to treat early cancer,5 and the drug's apparently low side-effect profile, led to the proposal that tamoxifen prophylaxis might be a suitable approach for reduction of the risk of breast cancer in high-risk women.6 A decrease of about 50% in the rate of new contralateral tumours with 5 years of tamoxifen treatment has been noted in several studies, which have been summarised in the Early Breast Cancer Trialists' Collaborative Group overview.7

These early results led to the initiation of a tamoxifen prevention pilot trial at the Royal Marsden Hospital, London, UK, in 1986.8, 9 That trial has now evolved into a full-scale prevention study. Three other studies started in 1992: the National Surgical Adjuvant Breast and Bowel Project P-1 Study (NSABP-P1),10 the Italian National trial,11 and the International Breast Cancer Intervention Study (IBIS) in the UK, Australia, New Zealand, and some European countries.12 Three of these studies have now published initial findings, with mixed results. A 50% decrease in breast-cancer incidence was observed in the North American trial, but little or no reduction was seen in the two European trials. The possible reasons for the differences in results have been the subject of much discussion, but no clear explanation is available. Results from all the trials are statistically compatible with a 30–40% decrease in incidence,13 but opinions vary substantially as to whether this effect is large enough to outweigh the established side-effects of tamoxifen, notably an increase in menopausal symptoms, vascular events, and endometrial abnormalities, including cancer.

Initial results are also available on the effect on breast-cancer incidence of another specific oestrogen-receptor modulator, raloxifene.14 These early results suggest a reduction of as much as 70%, and the side-effect profile is similar to that of tamoxifen, except possibly for endometrial cancer. A direct comparison of these two specific oestrogen-receptor modulators is the subject of a second North American trial.

Here we report the initial results from IBIS-I, comparing tamoxifen with placebo. The primary endpoint was frequency of breast cancer (including ductal carcinoma in situ). Predefined subgroups were oestrogen receptor status of the cancer, use of hormonal replacement therapy, and age (<50, ≥50 years) Secondary endpoints were other cancers, thromboembolic events, cardiovascular events, and cause-specific mortality.

Section snippets

Participants

Women aged 35–70 years were entered into the trial from April, 1992, until March, 2001 (figure 1). Eligible women had risk factors for breast cancer indicating at least a two-fold relative risk for ages 45–70 years, a four-fold relative risk for ages 40–44 years, and a roughly ten-fold relative risk for ages 35–39 years. Specific entry criteria are shown in table 1. Reasons for exclusion were any previous invasive cancer (except non-melanoma skin cancer), a previous deep-vein thrombosis or

Results

A total of 7139 women were included in the analysis (figure 1, table 1). The largest risk group was women who had two or more first-degree or second-degree relatives with breast cancer (62%). In all, 97% of the participants reported some family history, and 8% had a benign lesion associated with increased risk of breast cancer. The projected 10-year risk based on family history and other established risk factors is shown in figure 2. The yearly frequency of breast cancer in the absence of

Discussion

This study has confirmed that tamoxifen can reduce the risk of breast cancer in healthy women during the active treatment phase. The 32% reduction in risk seen in the study is consistent with the cumulative results when all of the chemoprevention trials are combined. The increased frequency of gynaecological problems, particularly the increased requirement for hysterectomy and oophorectomy, is of some concern. It may be a result of the observed higher proportions of women with abnormal vaginal

References (18)

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