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Systematic review
Tamoxifen, raloxifene and tibolone decrease risk of invasive breast cancer in healthy women but increase risk of thromboembolism (tamoxifen, raloxifene), endometrial cancer (tamoxifen) or stroke (tibolone)
  1. Victor G Vogel
  1. Correspondence to Victor G Vogel
    American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA; victor.vogel{at}

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Women who are at increased risk for breast cancer can be easily identified in clinical practice and may have very high lifetime probabilities of developing invasive breast cancer. Nelson and colleagues conducted a meta-analysis of eight clinical trials that examined the ability of selective oestrogen receptor modulators (SERMs) or tibolone to reduce the risk of invasive breast cancer in both premenopausal and postmenopausal women at various levels of risk of breast cancer. Tamoxifen and raloxifene are associated with a significant reduction in the risk of oestrogen receptor-positive invasive breast cancer. Tamoxifen is effective in both younger and older women, although side effects increase with age.

The authors state that data are lacking on doses, duration, timing and long-term side effects, although this statement is not entirely accurate. While it is true that only 20 mg of daily oral tamoxifen and 60 mg of daily oral raloxifene have been evaluated, the reported studies include tens of thousands of women, many treated for longer than 5 years (older women with raloxifene). There is also at least a two-decade span of ages at the time of enrolment in the trials, giving a broad understanding of the effect of the timing of the initiation of tamoxifen therapy in particular. There are not enough data on tibolone to make meaningful statements about its use.

The inclusion of the Italian trial in which half of the women had hysterectomy introduces some unfortunate heterogeneity into the analyses, as does the inclusion of the Royal Marsden trial that was a pilot study for the larger, more definitive International Breast Cancer Intervention Study I trial. Nevertheless, all the tamoxifen trials show remarkable similarity of outcomes in patients on two continents.

The risks and benefits of tamoxifen and other SERMs depend on age and on a woman's specific risk factors for breast cancer.1 2 The absolute risks from tamoxifen for endometrial cancer, stroke, pulmonary embolism and deep vein thrombosis increase with age, as does the protective effect of tamoxifen against fractures. Tamoxifen has its greatest clinical benefit with less severe side effects in women who do not have a uterus and in women at higher risk of breast cancer, such as those with atypical hyperplasia.3 SERMs should not be given to obese women or smokers or to women with a history of thromboembolic events.

Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer. Premenopausal women >35 years of age with Gail model risks of breast cancer >1.67% in 5 years or lobular carcinoma in situ can be offered tamoxifen for the reduction of breast cancer risk. When used to reduce the risk of breast cancer, tamoxifen should be given in a dose of 20 mg once daily, the dose used in the large randomised breast cancer risk reduction trials reported to date. Alternative doses and schedules have not been evaluated for safety or efficacy. No study has evaluated the optimum age at which to begin tamoxifen to reduce breast cancer risk; premenopausal women at increased risk derive the greatest net benefit because of the absence of increased risks for thromboembolic events or uterine cancer in this group.

In Europe, tamoxifen is not recommended as a preventive agent except possibly in very-high-risk women who want to avoid or delay prophylactic mastectomy. Because the risk of clotting increases with age, and because both stroke and pulmonary embolism are potentially life-threatening consequences of SERM therapy, careful consideration must be given to risks versus benefits in older postmenopausal women who are considering risk reduction.

The optimum duration of tamoxifen and raloxifene therapy is the most challenging remaining question. When raloxifene is used to manage osteoporosis, there is no limit to the duration of use. It is very unlikely that additional prospective clinical trials of SERMs for the reduction of breast cancer risk will be conducted in the future because of their prohibitive cost.


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  • Competing interests VGV was the protocol chairman for the NSABP Study of Tamoxifen and Raloxifene and an investigator for the NSABP Breast Cancer Prevention Trial, both included in the meta-analysis reviewed here.

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