The IBIS-1 Breast Cancer Prevention Trial: Initial Results

Abstract & Commentary

Synopsis: A large, placebo-controlled investigation of tamoxifen for prevention of breast cancer in high-risk women is reported. There was a 32% reduction in breast cancer but also an increase in thromboembolic events and all cause mortality in the tamoxifen treatment group. Thus, further analysis of this and other ongoing trials is necessary before the use of tamoxifen for breast cancer prevention can be commonly recommended.

Source: Cuzick J, et al. Lancet. 2002;360:817-824.

The International Breast Cancer Intervention Study (IBIS) performed by a collaborative group from the United Kingdom, Australia, New Zealand and some additional European countries initiated a trial in 1992 to determine the role of Tamoxifen in the prevention of breast cancer in women at high risk. In the current report they detail the preliminary results (after a median follow-up of 50 months) of a randomized, placebo-controlled trial of tamoxifen, 20 mg/day, in 7152 women aged 35-70 who were at increased risk of breast cancer. Of the 3578 women in the tamoxifen group, 69 breast cancers had been diagnosed, whereas 101 cases occurred in the 3566 in the placebo group (risk reduction of 32% [95% CI, 8-50]; P = 0.013). Age, degree of risk and the use of hormone-replacement therapy did not affect the reduction. Endometrial cancer was not significantly increased but thromboembolic events occurred more commonly (43 vs 17; odds ratio, 2.5 [1.5-4.4]; P = 0.001) in the tamoxifen-treated women. Of note, there was a significant excess of deaths from all causes in the tamoxifen group (25 vs 11; P = 0.028), analysis of the combined evidence indicated that the mortality from nonbreast cancer causes was not increased by tamoxifen. Cuzick and associates conclude that the overall risk-to-benefit ratio for the use of tamoxifen in prevention remains unclear, highlighting the need for continued follow-up of this and the other ongoing trials.

Comment by William B. Ershler, MD

The evidence that tamoxifen (or other anti-estrogens, such as Raloxifene) can inhibit breast cancer is mounting. Early reports demonstrated significant reduction of new contralateral tumors in tamoxifen treated patients with early breast cancer,1 and this effect has been estimated to result in approximately 50% fewer tumors with 5 years of treatment.2

There are at least 4 prevention trials currently ongoing. These include one at the Royal Marsden Hospital (London),3 the National Surgical Adjuvant Breast and Bowel Project, P-14, the Italian National trial5 and the IBIS trial, the initial findings of which are the subject of the current report. The findings from this and the other 3 are somewhat conflicting. In the IBIS trial there was a one-third reduction in breast cancer and in the NSABP trial the reduction was 50%. However, in the 2 European studies, little or no reduction in breast cancer incidence was observed. The results are difficult to reconcile, but the methodology was similar enough to allow a compiled analysis which allows an estimated 30-40% reduction in breast cancer incidence.6 Of course, the big question is whether this effect is large enough to outweigh the established side-effects of tamoxifen, notably an increase in menopausal symptoms, vascular events, and endometrial cancer.

There are also initial results available for Raloxifene7 suggesting a higher level of breast cancer reduction (70%) with a similar side effect profile, except, possibly for less endometrial cancer. Currently, a direct comparison of tamoxifen and Raloxifene in breast cancer prevention is underway. Similarly, aromatase inhibitors (such as anastrazole) have been shown to be more effective than tamoxifen in reducing recurrence of ER+ breast cancer and in preventing the appearance of new, contralateral tumors (58% reduction compared with tamoxifen).8 Drugs in this class do not have estrogen agonist properties present with tamoxifen, and thus are unlikely to be associated with endometrial cancer or thromboembolic disease. Thus, their use in the setting of breast cancer prevention for high-risk women will be of great interest.

The increased all-cause mortality observed in the IBIS trial has not been observed in the others, and in the all-trial combined data, it is not apparent. However, the significant increase in thromboembolic events is a common observation and warrants specific concern. In the IBIS trial (as well as in NSABP P-1) there was a small, but significant difference in thromboembolic deaths, occurring particularly after surgery or periods of immobilization. Thus, the suggestion that tamoxifen be held during these periods (surgery or immobilization for other causes) has been forwarded by Cuzick et al.

All considered, there is yet to be a consensus on the value of tamoxifen for prevention of breast cancer. Certainly, the data support its effectiveness in this capacity, but associated complications, particularly in thromboembolic events and endometrial cancer, are disconcerting and more long-term analysis of the current trials is warranted before this approach can be commonly recommended. 

Dr. Ershler is INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.


1. Cuzick J, Baum M. Lancet. 1985;1:282.

2. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451-1467.

3. Powles TJ, et al. Eur J Cancer. 1990;26:680-684.

4. Fisher B, et al. J Natl Cancer Inst. 1998;90:1371-1388.

5. Veronesi U, et al. Lancet. 1998;352:93-97.

6. Cuzick J. IARC Scientific Publication. 1996;136: 95-109.

7. Cauley JA, et al. Breast Cancer Res Treat. 2001;65: 125-134.

8. The ATAC Trialists’ Group. Lancet. 2002;359: 2131-2139.