Biological Basis For Tamoxifen As A Breast Cancer Preventive

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Tamoxifen was selected for testing as a preventive based on (1) animal studies that demonstrated it could prevent carcinogenesis,49-52,103 (2) extensive clinical experience that showed few serious side effects, and (3) a beneficial profile of estrogen-like action in maintaining bone density and reducing circulating cholesterol. Ta-moxifen was already known to reduce the incidence of contralateral breast cancer47 and to have a favorable toxicity profile, making the drug the primary agent to test in high-risk women.

Sporadic reports19,104 and placebo-controlled randomized trials20,105 demonstrated that ta-moxifen can increase bone density in the lumbar spine, forearm, and neck of the femur by 1%-2%. Although the increases are modest compared to the results obtained with estrogen or biphosphonates (5% increase in bone density), tamoxifen produced a marginal decrease in hip and wrist fractures as a secondary end point in the breast cancer prevention trial.106

Tamoxifen reduces circulating choles-terol.21,22 Low-density lipoprotein cholesterol is reduced by about 15%, and high-density lipoprotein cholesterol is maintained. It is hypothesized that this magnitude of fall in circulating cholesterol is a good surrogate marker for protection from coronary heart disease. There is evidence that women who have been treated with 5 years of adjuvant tamoxifen for breast cancer have a reduced incidence of fatal myocardial infarction.107,108 Conversely, a large study in the

United States of 5 or more years of adjuvant ta-moxifen found no statistically strong evidence for protection from coronary heart disease.109 Nevertheless, the incidence of coronary heart disease increased once tamoxifen treatment was stopped, and there was no evidence for a detrimental effect of tamoxifen. Only a prospective, randomized trial in a population with cardiac risk factors would provide accurate data supporting cardioprotection from tamoxifen.

Tamoxifen produces partial agonist action in the rat uterus,56 but until the late 1980s there was little information about its actions in the normal human uterus. It is now clear that a variety of en-dometrial changes occur in unselected populations of women.110 The most significant finding is an increase in the stromal component, rather than endometrial hyperplasia.111,112 Laboratory data suggesting that tamoxifen has the potential to encourage the growth of preexisting disease harbored in the uterus67,68 provoked an intense investigation of the rates of endometrial cancer detection in women using adjuvant tamoxifen treatment for breast cancer. It is clear from the results of the tamoxifen prevention trial106 that ta-moxifen does not cause an excess of endometrial cancer in premenopausal women but does increase risk by three- to fourfold in post-menopausal women. This is consistent with the fact that women harbor four to five times the level of endometrial cancer than is detected clini-cally.113 In other words, the increase in the detection of endometrial cancer from 1 per 1000 women per year to 3 per 1000 per year is consistent with the known rate of occult disease. Most importantly, the stage and grade of endometrial cancers observed in women taking tamoxifen are the same as those in the general population.106,114 Bernstein and colleagues115 analyzed the incidence of endometrial cancer associated with ta-moxifen therapy with known risk factors for the disease. Women taking tamoxifen who developed endometrial cancer were obese or had previously taken estrogen-replacement therapy. This population of women would warrant careful evaluation prior to the use of tamoxifen.

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