Re-evaluation of the therapeutic role of Hormone replacement therapy in breast cancer survivors necessitates consideration of the combined, systemic effects of tamoxifen and Hormone replacement therapy, particularly on breast cancer cell proliferation. Concern that Hormone replacement therapy may antagonize the anti-neoplastic effect of tamoxifen in breast cancer survivors has not been evaluated in controlled trials and therefore the only evidence available upon which to base any clinical recommendations is that from the tamoxifen chemoprevention trials.

Following the observation of a 50% reduction in the incidence of contralateral breast cancer in women treated with adjuvant tamoxifen therapy, three randomized tamoxifen chemoprevention trials in women at high risk of developing breast cancer were initiated in the United States, Italy, and the United Kingdom. The largest of these, the National Surgical Adjuvant Breast and Bowel Project P-l Study (NSABP P-l), reported a 69% reduction in the incidence of Oestrogen receptor-positive invasive breast cancer (relative risk 0.31; 95% confidence interval 0.22-0.45) but no difference in the occurrence of Oestrogen receptor-negative disease and a 50% reduction in the incidence of non-invasive breast cancer (p < 0.002) after a median follow-up of 4.5 years. As a result this trial was stopped prematurely and women taking placebo were given the opportunity to commence tamoxifen. In the absence of any long-term mortality data, however, it is not possible to determine whether this reported benefit of tamoxifen reflects treatment of subclinical disease or a true reduction in the risk of developing breast cancer.

Interim analyses of the Italian and United Kingdom trials have not shown tamoxifen to reduce breast cancer risk. Although it has been argued that these smaller trials are not powerful enough to detect any true difference, the fact that the use of Hormone replacement therapy was permitted in these trials, and not the NSABP P-l trial, has been offered as an explanation of the opposing results. Hormone replacement therapy, however, did not appear to exert an adverse effect on breast cancer

incidence in the 42% of women taking it during the Royal Marsden Hospital trial but the Italian study reported that tamoxifen reduced the incidence of breast cancer in the 14% of women who received Hormone replacement therapy (hazard ratio 0.13; 95% confidence interval 0.02-1.02). Since the European trials have not completed follow-up and the use of Hormone replacement therapy in this context was not a primary hypothesis, and nor was its allocation randomized, these preliminary results should be treated with caution and no definitive conclusions should be drawn.

Tamoxifen has a diverse range of clinical effects owing to its complex endocrinological profile. Anti-oestrogenic, partial oestrogen-agonist, and oestrogen-independent activities have all been described and evidence is accumulating that the level of circulating endogenous oestrogen influences the biological activity of tamoxifen. In postmenopausal women, tamoxifen exerts predominantly oestrogenic effects on bone mineral density, serum low density lipoprotein (low density lipoprotein) cholesterol levels, vaginal epithelium, and the endometrium, where it is associated with a 2 — 3-fold increase in the risk of developing endometrial cancer. In premenopausal women, however, tamoxifen appears to behave as an anti-oestrogen in that it promotes bone demineralization, has no significant effect on serum cholesterol levels, and may not induce vaginal epithelial cell maturation or endometrial proliferation.

Preliminary data from the tamoxifen chemoprevention studies suggest that tamoxifen and Hormone replacement therapy have a cumulative beneficial effect on femoral bone mineral density, with an annual reported increase of 4%. In contrast, animal studies have shown that the bone-sparing effect of tibolone is prevented by anti-oestrogens.Reports that the oestrogenic effect of tamoxifen on the endometrium is inversely correlated with age suggest that the oestrogen component of combined Hormone replacement therapy may protect postmenopausal women against the development of tamoxifen-induced endometrial pathology. Using changes in serum lipoprotein levels as a surrogate for arterial disease events, there does not appear to be any additional benefit of adding Hormone replacement therapy to tamoxifen.

The selective oestrogen receptor modulator (SERM) raloxifene, which is an analogue of tamoxifen, has been reported to reduce significantly the incidence of postmenopausal Oestrogen receptor-positive breast cancer in a meta-analysis of nine randomized, placebo-controlled trials (relative risk 0.46; 95% confidence interval 0.28-0.75). The most recent data from the ongoing Multiple Outcomes of Raloxifene Evaluation (MORE) study have indicated a relative risk of developing breast cancer of 0.35 (95% confidence interval 0.21-0.58) with a median follow-up of 40 months. However, these results should be treated with caution, since osteoporosis prevention and not breast cancer incidence or survival was the primary end point of these trials. A breast cancer chemoprevention trial comparing tamoxifen and raloxifene is planned in the United States, in which breast cancer incidence and mortality will be the main outcome measures. In common with tamoxifen and other SERMs under development, raloxifene is ineffective in treating oestrogen deficiency symptoms and may even induce them and therefore has no role in the treatment of vasomotor symptoms in breast cancer patients. No clinical data exist for cases in which raloxifene and Hormone replacement therapy have been prescribed together.

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