Alternate antiestrogens and approaches to the prevention of breast cancer

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Abstract
The biological rationale and extensive clinical experience with the breast cancer drug tamoxifen make it the agent of choice for testing as a breast cancer preventive. However, concerns (Jordan and Morrow, Eur J Cancer, in press) about development of endometrial cancer in patients and liver tumors in rats with tamoxifen has encouraged the investigation of other antiestrogens. At present no compounds are available to replace tamoxifen, but two triphenylethylenes, toremifene and droloxifene, have been tested in postmenopausal women to treat advanced breast cancer. The response rates are similar to those observed with tamoxifen (i.e., approximately 35% [CR + PR] in unselected patients), although dosage regimens of the new antiestrogens are higher than the 20 mg tamoxifen required daily. Doses of up to 200 mg toremifene daily are being tested and studies use up to 100 mg droloxifene daily. Side effects appear comparable, but neither droloxifene nor toremifene produce liver tumors in rats. Tamoxifen produces DNA adducts, whereas toremifene and droloxifene appear to be only weakly active. A new tamoxifen analogue, idoxifene, is entering clinical trial. The drug is designed to be metabolically stable so that there will be low carcinogenic potential. In contrast, a novel strategy may be considered to be of value to protect women from developing breast cancer. It is known from laboratory and clinical studies that antiestrogens protect bone and prevent rat mammary cancer. One compound, raloxifene, is being tested as an agent to treat osteoporosis. If the drug becomes generally available to prevent osteoporosis in postmenopausal women, a beneficial side effect may be a reduction in breast cancer risk. This broad-based strategy may prove more effective than focusing on small groups of women with a high risk for breast cancer alone. Protection from breast cancer may be as an advantageous side effect from the successful treatment of other diseases in women.