Tamoxifen for the Prevention of Breast Cancer in High-Risk Women

The International Breast Cancer Intervention Study I (IBIS-I) was designed to investigate the use of tamoxifen in preventing breast cancer in women with a higher risk of developing the disease. Recruitment of women to IBIS-I ended in March 2001 and it recruited 7154 women from 36 centres in 9 countries. The results of the study showed that tamoxifen reduced the incidence of breast cancer by one third in these high risk women but with some serious side effects. IBIS-II was designed to continue the work started in IBIS-I by examining the role of anastrozole in the prevention of breast cancer which we hope will reduce breast cancer by even more than tamoxifen with less serious side effects.

Established in 1992, the IBIS-I Study investigated the efficacy of tamoxifen (a hormonal drug used to prevent breast cancer) versus a placebo drug (taken daily for five years) in terms of reduction of breast cancer incidence in pre and postmenopausal women at high risk of developing breast cancer. It was a double-blind, randomised placebo-controlled trial that recruited 7,154 women internationally (of which 4,277 were UK participants), aged 35-70 years. The primary outcome measure was the incidence of breast cancer, including ductal carcinoma in situ (cancer cells in the lining of the breast milk duct) and side effects present in the patients were also investigated.

Recruitment to the study completed in 2001 and the intervention (placebo/tamoxifen) ended in 2007. In early 2008 the Research Ethics Committee (REC) approved the conversion of IBIS-I to an epidemiological cohort study. During 2007-2016 participants were followed-up via an annual postal questionnaire.

In 2002, initial results found that tamoxifen reduced the risk of invasive breast cancer by 31%. Mortality from non-breast cancer causes was not increased by tamoxifen. However, the analysis concluded that the overall risk/benefit ratio for the use of tamoxifen in prevention remained unclear and that continued follow-up of trial participants was essential. A 2007 analysis on long-term tamoxifen prophylaxis for breast cancer confirmed the preventive effect of tamoxifen in terms of breast cancer incidence and that this was constant for the entire follow-up period. No reduction in size of benefit was observed for up to ten years following participant randomisation. Additionally, tamoxifen-related side effects such as thrombo-embolism were not increased anymore after the 5-year treatment period. These results therefore demonstrate that the benefit-to-risk ratio of tamoxifen improves with increasing duration of follow-up. Thus, how much additional benefit will be seen long-term remains an important question.

Eligibility Criteria:
Inclusion criteria:

The entry criteria are based on a relative risk of at least two-fold for women aged 45-70 years, four-fold for women aged 40-44 years and ten-fold for women aged 35-39 years.

Age 45-70 years

1. First degree relative who developed breast cancer at age 50 or less
2. First degree relative who developed bilateral breast cancer
3. Two or more first or second degree relatives who developed breast cancer
4. Nulliparous and a first degree relative who developed breast cancer
5. Benign biopsy with proliferative disease and a first degree relative who developed breast cancer
6. Lobular carcinoma in situ
7. Atypical ductal or lobular hyperplasia in a benign lesion

19)Women at high risk who do not fit into the above categories (risk equivalent)\*

\* These women must have clearly apparent family history indicating at least two fold increased risk of breast cancer.

Age 40-44 years 8) Two or more first or second degree relatives who developed breast cancer at age 50 or less 9) First degree relative with bilateral breast cancer who developed the first breast cancer at age 50 or less 10) Nulliparous and a first degree relative who developed breast cancer at age 40 or less 11) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer at age 40 or less 12) Lobular carcinoma in situ 13) Atypical ductal or lobular hyperplasia in a benign lesion 14) Women at high risk who do not fit into the above categories (risk equivalent)\*

\* These women must have clearly apparent family history indicating at least four fold increased risk of breast cancer.

Age 35-39 years 15) Two or more first degree relatives who developed breast cancer at age 50 or less 16) First degree relative with bilateral breast cancer who developed the first breast cancer at age 40 or less 17) Lobular carcinoma in situ 18) Women at high risk who do not fit into the above categories (risk equivalent)\*

Exclusion criteria:

1. Pregnant, or at pregnancy risk. If necessary, pre and peri menopausal women must use non-hormonal contraception during the trial.
2. Any previous cancer (except non-melanoma skin cancer or in situ cancer of the cervix).
3. Life expectancy of less than 10 years or other medical condition more serious than the risk of breast cancer.
4. Psychologically and physically unsuitable for five years tamoxifen/placebo therapy.
5. Current treatment with anti-coagulants.
6. Previous deep vein thrombosis or pulmonary embolus.
7. Current tamoxifen use.