HRT Opposed to Low-Dose Tamoxifen (HOT Study): Rationale and Design
The rationale for the HOT study is mainly based on the findings of the Italian Tamoxifen Prevention Study, where 5,408 healthy hysterectomized women aged 35–70 years were randomized to 20 mg/day of tamoxifen or placebo for 5 years. After 81.2 months media
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Abstract The rationale for the HOT study is mainly based on the findings of the Italian Tamoxifen Prevention Study, where 5,408 healthy hysterectomized women aged 35-70 years were randomized to 20 mg/day of tamoxifen or placebo for 5 years. After 81.2 months median follow-up, 79 breast cancers occurred (34 on tamoxifen versus 45 on placebo, p=0.215). In the subgroup of 1,580 women who used estrogen replacement therapy (ERT) at some point during the study, 23 breast cancers were observed: 17 on placebo and 6 on tamoxifen (hazard ratio=0.35, 95% CI, 0.14-0.89). Pharmacokinetic and pharmacodynamic (surrogate endpoint biomarkers) studies showed that a lower dose of tamoxifen (such as 5 mg/day) does not affect the drug's activity on several biomarkers of both cardiovascular and breast cancer risk. We therefore propose a multicenter placebo-controlled phase III trial in postmenopausal healthy women on hormone replacement therapy (HRT) to assess whether the combination of HRT and low-dose tamoxifen retains the benefits while reducing the risks of either. A number of different observations indicate that the combination of hormone replacement therapy (HRT) and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. While epidemiological evidence suggests that HRT can substantially increase quality as well as length of life, a prolonged use of HRT can also increase the risk of developing breast cancer, particularly with the combination of estrogens and progestins. The increased risk has been associated with an increased expression of estrogen receptors in the healthy breast tissue, thus leading to an enhanced sensitivity to estrogen signal. Thus, the addition of a SERM which may be capable of reducing this growth promoting effect on the breast appears rationale for women's health maintenance. A post hoc analysis of the Italian study of Breast Cancer Chemoprevention with tamoxifen showed a borderline significant reduction of breast cancer among women who were
Recent Results in Cancer Research, Vol. 163 © Springer-Verlag Berlin Heidelberg 2003
HRT Opposed to Low-Dose Tamoxifen (HOT Study)
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on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Although the study was regarded as being affected by a high drop-out rate [1], a comparison of the three primary prevention trials of tamoxifen indicates that, in fact, the number of discontinuations for reasons other than major events was 20.7%, 28.8%, and 35.5%, in the Italian, American, and Marsden trials, respectively [2]. In the Italian trial, the drop-out rate was higher during the first year of recruitment and plateaued thereafter (2% per month in the first year versus 1% in years 2-5). Since most women who left the study voluntarily did so mainly because of menopausal symptoms, the combination of tamoxifen and estrogen replacement therapy (ERT) might reduce tamoxifen side effects. Indeed, the rate of voluntary withdrawals was different according to ERT use: co
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