Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial

Jack Cuzick,Ivana Sestak,Simon Cawthorn,Hisham Hamed,Kaija Holli,Anthony Howell,John F Forbes

doi:10.1016/s1470-2045(14)71171-4

Abstract

SummaryBackgroundFour previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation.MethodsIn the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com, number ISRCTN91879928.FindingsBetween April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16·0 years (IQR 14·1–17·6), 601 breast cancers have been reported (251 [7·0%] in 3579 patients in the tamoxifen group vs 350 [9·8%] in 3575 women in the placebo group; hazard ratio [HR] 0·71 [95% CI 0·60–0·83], p<0·0001). The risk of developing breast cancer was similar between years 0–10 (226 [6·3%] in 3575 women in the placebo group vs 163 [4·6%] in 3579 women in the tamoxifen group; hazard ratio [HR] 0·72 [95% CI 0·59–0·88], p=0·001) and after 10 years (124 [3·8%] in 3295 women vs 88 [2·6%] in 3343, respectively; HR 0·69 [0·53–0·91], p=0·009). The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer (HR 0·66 [95% CI 0·54–0·81], p<0·0001) and ductal carcinoma in situ (0·65 [0·43–1·00], p=0·05), but no effect was noted for invasive oestrogen receptor-negative breast cancer (HR 1·05 [95% CI 0·71–1·57], p=0·8).InterpretationThese results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention.FundingCancer Research UK (UK) and the National Health and Medical Research Council (Australia).

Highlights

A recently published metaanalysis of all prevention trials investigating selective oestrogen receptor modulators has shown that these drugs significantly reduce the incidence of all breast cancer in the first 10 years of follow-up
The HR for tamoxifen was 0·67, but this was maintained for the entire 10-year period (HR 0·62 [95% CI 0·53–0·73] in years 0–5 and 0·78 [0·62–0·97] in years 5–10), whereas little followup information was available after 5 years for the other selective oestrogen receptor modulators
With the exception of the Royal Marsden trial, in which median follow-up was 13 years,5 follow-up has been limited to 10 years or less for all other reports. In this Article, we report an updated analysis of the International Breast cancer Intervention Study I (IBIS-I) trial, which remains largely masked to treatment allocation

Summary

Introduction

Breast cancer remains the most common type of cancer in women, with an estimated incidence of 1·6 million cases per year worldwide. Tamoxifen is a well-established and effective treatment for oestrogen receptor-positive breast cancer. Four large randomised clinical trials have shown that tamoxifen reduces the incidence of oestrogen receptor-positive breast cancer in women at high risk of developing the disease. A recently published metaanalysis of all prevention trials investigating selective oestrogen receptor modulators has shown that these drugs significantly reduce the incidence of all breast cancer (including ductal carcinoma) in the first 10 years of follow-up (hazard ratio [HR] 0·62 [95% CI 0·56–0·69]). The HR for tamoxifen was 0·67 (95% CI 0·59–0·76), but this was maintained for the entire 10-year period (HR 0·62 [95% CI 0·53–0·73] in years 0–5 and 0·78 [0·62–0·97] in years 5–10), whereas little followup information was available after 5 years for the other selective oestrogen receptor modulators.10The International Breast cancer Intervention Study I (IBIS-I) was initiated in 1992 and recruited women at high risk of developing breast cancer to receive oral tamoxifen (20 mg daily) or matching placebo. The initial report showed a significant reduction (odds ratio [OR] 0·68 [95% CI 0·50–0·92]) for all types of breast cancer (including ductal carcinoma in situ) after a median followup of 4·2 years (IQR 2·67–5·58).. After a median follow-up of 8 years (IQR 6·35–9·61), an updated report showed the significant reduction for all types of invasive breast cancer continued (risk ratio 0·73 [95% CI 0·58–0·91]) with tamoxifen.. After a median follow-up of 8 years (IQR 6·35–9·61), an updated report showed the significant reduction for all types of invasive breast cancer continued (risk ratio 0·73 [95% CI 0·58–0·91]) with tamoxifen.7 In both reports, a risk reduction by tamoxifen was only seen for oestrogen receptor-positive breast cancer and ductal carcinoma in situ.

Methods

Results

Conclusion