SERMs are selective estrogen receptor modulators. Estrogens stimulate the cells to divide and grow. SERMS can mimic estrogen, which means that cells think the SERM is estrogen, and, depending on the tissue, either promote estrogen effects or stop them. For example, SERMs will either stimulate a cell or block its growth. This seems to depend on which tissues are involved and which SERM is used. Tamoxifen and raloxifene are both pill medications that are SERMs and other SERMs are in the process of being developed.
Tamoxifen
Tamoxifen was the first SERM produced, and has been in use in clinics for 21 years, and in clinical trials for 30 years. Initially it was used in metastatic disease, but we know that it is effective both in reducing recurrence of primary breast cancer and improving overall survival in both postmenopausal and premenopausal women. As well, it has been shown to reduce the incidence of local recurrence of breast cancer in the contralateral breast. And more recently it has been approved in the United States as a prevention strategy. However, it does have side effects.
Because tamoxifen is not a perfect drug, researchers have been trying to develop a SERM that will have the beneficial effects of tamoxifen without some of its negative side effects. Attempts have been made to develop a SERM that will act like estrogen where it is needed but not stimulate tissues where estrogen may be dangerous.
The ideal SERM would act like estrogen on the bones to protect against osteoporosis, as well as affect lipid and cholesterol levels to protect against heart disease. The drug would also stimulate the estrogen receptors in the brain, as there is evidence for estrogen's positive effect on memory, and it would keep skin and mucous membranes healthy.
However, there are concerns about estrogen's stimulatory effects on breast tissue and on the endometrium, which may increase the incidence of breast cancer and cancer of the uterus. Therefore, the ideal SERM would act as an antiestrogen on those tissues and protect against cancer.
Raloxifene
Raloxifene is very similar to tamoxifen and has many of the same side effects, such as hot flushes, vaginal discharge, and an increased risk of clotting resulting in strokes, pulmonary embolus, and deep vein thrombosis. It does appear that raloxifene stimulates the uterus less than tamoxifen so there may be a lower incidence of endometrial cancer.
Raloxifene has not been studied in premenopausal women, but a small study has just been initiated by the US National Cancer Institute to look at its safety in this group. Raloxifene is an exciting new drug for osteoporosis but its role in cancer prevention needs to be assessed.
Clinical studies
Recently the results of a North American trial were reported in which over 13,000 women who were at high risk of developing breast cancer, but had not had a diagnosis of cancer, were randomly given the drug tamoxifen or a placebo (i.e., a sugar pill) for a period of 5 years. At the end of the 5 years, the incidence of breast cancers was reduced by 49% in the group receiving tamoxifen, however, many women experienced side effects that were sometimes severe. This was, however, the first indication that we could successfully reduce the incidence of breast cancer with a medication.
Raloxifene (Evista®) is a new SERM that was developed to treat osteoporosis. Large randomized trials of raloxifene versus placebo (i.e. sugar pills) were conducted in women with osteoporosis and the results showed that the women receiving raloxifene had a lower incidence of breast cancer. These results were similar to the results of the tamoxifen prevention study.
These trials were not designed to assess breast cancer, but rather osteoporosis, so the test groups were not compatible. For example, the average age in the rolaxifene trials was older than those in the tamoxifen trials which could account for some of the findings. Therefore, this data must be viewed as an interesting observation that requires further investigation. The trials do not prove that raloxifene is either a breast cancer prevention drug or a drug to use as a substitute or tamoxifen. These trials do provide enough data to start investigating raloxifene. A large study of 22,000 women is being initiated in 400 centers in North America for postmenopausal women who have not had breast cancer but who have an increased risk of developing cancer.