Powles and coworkers162 recruited high-risk women aged 30-70 to a placebo-controlled trial using 20 milligrams of tamoxifen daily for up to 8 years. Each participant had at least one first-degree relative with breast cancer under age 50, a first-degree relative affected at any age plus an additional affected first- or second-degree relative, or a first-degree relative with bilateral breast cancer. Women with a history of benign breast biopsy and an affected first-degree relative of any age were also eligible. Women with a history of venous thrombosis, any previous malignancy, or an estimated life expectancy of fewer than 10 years were excluded.160,163 A total of 2494 women consented to participate in the study, and 23 were excluded from final analysis due to the presence of preexisting ductal carcinoma in situ (DCIS) or invasive breast carcinoma. The trial was undertaken to evaluate the problems of accrual, toxicity, compliance, and safety of tamoxifen prior to a large national, multicenter trail of chemoprevention. The stated goal was to evaluate the feasibility of a volunteer trial of 20,000 patients throughout the United Kingdom and Australia; however, breast cancer incidence was also analyzed.160
Acute toxicity was low for participants in the pilot study, and compliance remained correspondingly high: 77% of women on tamoxifen and 82% of women on placebo remained on medication at 5 years.163 There was a significant increase in hot flashes (34% vs. 20%, p < 0.005), mostly in premenopausal women; vaginal discharge (16% vs. 4%, p < 0.005); and menstrual irregularities (14% vs. 9%, p < 0.005). At the most recent follow-up, 320 women had discontinued tamoxifen and 176 had discontinued placebo prior to the study's completion.160
At 70 months, no significant difference in the incidence of deep vein thrombosis or pulmonary embolism was observed between groups.163 A detailed analysis of other coagulation parameters in a sequential subset of women found no significant changes in protein S, protein C, or cross-linked fibrinogen degradation products. A significant fall in total plasma cholesterol occurred within 3 months and was sustained over 5 years of treatment.163 The decrease affected low-density lipoprotein, with no change in apolipo-proteins A and B or high-density lipoprotein cholesterol.
In contrast, tamoxifen exerted antiestrogenic or estrogenic effects on bone density, depending on menopausal status. In premenopausal women, early findings demonstrated a small but significant (p < 0.05) loss of bone in both the lumbar spine and hip at 3 years. In contrast, postmenopausal women had increased bone mineral density in the spine (p < 0.005)
and hip (p < 0.001) compared to untreated
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