Selective estrogen receptor modulators, commonly referred to as SERMS, are a class of compounds that interact with subsets of estrogen receptors alpha and beta. SERMS are different from normal human estrogen because they bind to some tissues, repel others and display neutral activity in other tissue types. Normal human estrogen, by contrast, affects most tissues in a similar manner.
Based on their ability to distinguish among different estrogen receptors in the body, SERMS are being studied for use in the prevention and treatment of a number of diseases, including cancer. The use of SERMS in cancer is particularly aimed at hormone-dependent cancers and some breast cancers. The SERMS work as antagonists in this setting, by occupying receptors and making them unavailable for stimulation by human estrogen.
Tamoxifen
Tamoxifen, also known as Nolvadex, is the oldest SERM in continuous use in the clinic. Its anti-estrogen activity was first discovered in 1962 and it was first evaluated as a contraceptive. Although it failed as a contraceptive, researchers noticed that the drug had an effect on certain tissue types, including breast tissue, which led to speculation that it might be effective as a cancer therapeutic.
Initial experiments showed that tamoxifen could inhibit the growth of human breast cancer cells in animals and in tissue culture by depriving the cells of estrogen. Based on these results, clinical trials for women with advanced breast cancer were conducted and were successful, leading to FDA approval of the drug for advanced disease in 1977.
Tamoxifen was then examined for its ability to prolong survival and prevent recurrence in patients who had undergone surgery, and these tests were successful. It was also tested in women with cancers that had spread to their lymph nodes but were less advanced than those of the women enrolled in initial trials. Tamoxifen was approved for both applications by the FDA in the early 1980s.
Minor side effects of tamoxifen include menopausal symptoms such as hot flashes, irregular periods, vaginal irritation, headaches and fatigue. More serious side effects include increased risks of endometrial cancer, uterine sarcoma, venous thrombosis, pulmonary embolism and cataracts. These side effects complicate the use of tamoxifen in prevention. Although tamoxifen has been demonstrated to reduce breast cancer risk by 49 percent in high-risk women, fewer than 20 percent of these women take it as a preventive agent due to its side effects.
Newer SERMS
In September 2007, the FDA approved another SERM, raloxifene, also known as Evista, for the reduction of invasive breast cancer among women with either osteoporosis or women considered to be at high risk for invasive breast cancer. Raloxifene had been previously approved for the prevention of osteoporosis in postmenopausal women.
The FDA based its approval on results of STAR (Study of Tamoxifen and Raloxifene), which enrolled more than 19,000 women to test the effectiveness of tamoxifen and raloxifene in reducing the chance of developing breast cancer. Raloxifene reduced the risk of invasive breast cancer by 50 percent. Compared with tamoxifen, raloxifene reduced the risk of subsequent uterine cancer by an additional 36 percent and blood clots by an additional 29 percent.
Arzoxifene, another SERM, showed anti-estrogenic activity and a blocking of tumor growth in laboratory studies, but a Phase III clinical trial, reported in November 2007, showed that arzoxifene was not any better than tamoxifen. The FDA has not yet approved this drug for use.