Tamoxifen (also known as Nolvadex) is a synthetic compound similar to estrogen. It mimics the action of estrogen on the bones and uterus, but blocks the effects of estrogen on breast tissue.
Tamoxifen is used as adjuvant hormonal therapy immediately after surgery in early stages of breast cancer and in advanced metastatic breast cancer (stages III and above) in women and men. Adjuvant therapy is treatment added to curative procedures (such as surgery) to prevent the recurrence of cancer. Although tamoxifen is also used to treat malignant melanoma , brain tumors and uterine cancer, these uses are not indicated on the product label. According to FDA guidelines, women who are at high risk of developing breast cancer may take tamoxifen to reduce their risk; however, prolonged use may increase the risk of developing endometrial cancer (also called uterine cancer).
First synthesized in 1966 in Great Britain as an antifertility drug, tamoxifen was evaluated to treat cancer in 1970. In 1998, the United States Food and Drug Administration approved tamoxifen to reduce the risk of breast cancer. While tamoxifen can be given to patients alone, it is often given in combination with other chemotherapeutic drugs such as fluorouracil .
Tamoxifen belongs to a family of compounds called antiestrogens . Antiestrogens are used in cancer therapy by inhibiting the effects of estrogen on target tissues. Estrogen is a steroid hormone secreted by the female ovary. Depending on the target tissue, estrogen can stimulate the growth of female reproductive organs and breast tissue, play a role in the female menstrual cycle, and protect against bone loss by binding to estrogen receptors on the outside of cells within the target tissue. Antiestrogens act selectively against the effects of estrogen on target cells in a variety of ways, thus they are called selective estrogen receptor modulators (SERMs).
Tamoxifen selectively inhibits the effects of estrogen on breast tissue, while selectively mimicking the effects of estrogen on bone (by increasing bone mineral density) and uterine tissues. These qualities make tamoxifen an excellent therapeutic agent against breast cancer. Although researchers are unclear of the precise mechanism by which tamoxifen kills breast cancer cells, it is known to compete with estrogen by binding to estrogen receptors on the membrane of target cells, thus limiting the effects of estrogen on breast tissue. Tamoxifen may also be involved in other anti-tumor activities affecting oncogene expression, promotion of apoptosis (cancer cell death) and growth factor secretion. (Growth factors are hormones that influence cell division and proliferation, and these hormones can encourage cancers to grow.)
In 2000, the STAR (Study of Tamoxifen and Raloxifene ) study began. The purpose of this double-blind study is to evaluate the use of tamoxifen and raloxifene (another type of SERM) over a five-year period in 22, 000 postmenopausal women 35 years or older who are at high risk for developing breast cancer. The study will evaluate both the effectiveness and degree of side effects to determine which drug is most beneficial. Women interested in participating in this program can contact the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Another National Cancer Institute study that is relevant to the discussion of tamoxifen is the Breast Cancer Prevention Trial. This trial began in 1992 and was designed to see if tamoxifen was effective as a preventative against breast cancer. The study was also a double-blind study, and participants were receiving either tamoxifen or a placebo (an inactive pill that looks like tamoxifen). About four years into the study, in 1998, researchers reported that the women receiving tamoxifen:
- had 49% fewer diagnoses of invasive breast cancer
- had 50% fewer diagnoses of noninvasive breast cancer (such as ductal carcinoma in situ)
- had fewer fractures of the hip, wrist, and spine
- had more than twice the chance of developing endome-trial cancer, and
- had increased chance of developing blood clots, both in the lung and in major veins
when compared to the women receiving the placebo. Because of these findings, in 1998, the FDA approved the use of tamoxifen as a breast cancer preventative for high-risk women, as mentioned above.
Tamoxifen is taken orally and is available in 10-and 20-milligram (mg) tablets. Although it can be given within the range of 10 mg to 80 mg, the typical dosage is 20 to 40 mg daily for both adult females and males using tamoxifen for treatment of advanced breast cancer. At this dosage, there is an observed 30% response rate with complete remission in 10% of patients. It appears that patients 60 years and older have higher response rates. For patients using tamoxifen for adjuvant therapy after surgery, the typical dosage is 20 mg once daily for two to five years following surgery. Women at high risk for developing breast cancer usually take 20 mg daily for five years. If a dosage is missed, patients should not double the next dosage. Instead, they should go back to their regular schedule and contact their doctor.
Tamoxifen is not recommended for use in children. Women who are pregnant or nursing should not use this drug since it has several side effects that, although rare, can be severe. It is known to cause miscarriages and birth defects. Women are encouraged to use birth control while taking tamoxifen. However, oral contraceptives can negatively alter the effects of tamoxifen. Therefore, patients should explore other, nonhormonal birth control options.
Great care should be exercised when tamoxifen is used with warfarin , an anticoagulant, because tamoxifen can interfere with the effects of warfarin, and dose adjustments may be necessary. Patients who are predis-posed to the formation of thromboembolisms, or blood clots, should use tamoxifen with caution. It should be noted that smokers are at a higher risk for thromboembolism than nonsmokers.
Although tamoxifen is usually well tolerated by patients, there are some side effects. About 25% of patients experience side effects such as mild nausea, vomiting, hot flashes, weight gain, bone pain , and hair thinning. These side effects are usually not severe enough to stop therapy. Patients using tamoxifen for long periods of adjuvant therapy may face unwanted effects years into therapy, which warrant discontinued use of the drug. Some of these effects include possible increased risk of developing liver adenoma as well as increased risk of uterine (endometrial) cancer; eye problems such as retinal lesions, macular edema and corneal changes (most resolve themselves after use is discontinued); neurological problems such as depression , dizziness, confusion, and fatigue ; and genital problems such as vaginal bleeding, vaginal discharge, and endometriosis.
Tamoxifen can interfere with the anticoagulant drug warfarin , and if these two drugs are used together, patients will need to be monitored very closely. Oral contraceptives can also interfere with the action of tamoxifen.
See Also Toremifene; Nausea and vomiting; Alopecia
Sally C. McFarlane-Parrott
—an agent preventing the coagulation (clotting) of blood
—a type of cell death where cells are induced to commit suicide
—a study where neither the participant nor the physician know who has received the drug in question
—a gene whose presence can cause cancer; usually arising through mutation of a normal gene
—a blood clot that blocks a blood vessel in the cardiovascular system
Tamoxifen, a selective estrogen-receptor modulator, is an oral medication exhibiting both estrogen agonist and antagonist effects. Tamoxifen can be used to treat advanced breast cancer, to decrease the risk of recurrence of early-stage breast cancer, and for breast cancer prevention. Patients with an early-stage breast cancer with expression of the estrogen or progesterone receptors, or for whom no receptor result is known, benefit from five years of tamoxifen treatment. This treatment has been shown to decrease the annual risk of recurrence of breast cancer, and to decrease the risk of contralateral breast cancer by 47 percent. Tamoxifen has been studied as breast cancer prevention in patients at elevated risk of developing breast cancer (five-year risk of 1.66% or higher), decreasing the chance of developing an invasive or noninvasive breast cancer by approximately 50 percent. Newer antiestrogens, such as raloxifene, may have fewer side effects and similar effectiveness. Studies are underway to determine their effectiveness.
(see also: Breast Cancer; Breast Cancer Screening; Preventive Medicine )
Osborne, C. K. (1998). "Tamoxifen in the Treatment of Breast Cancer." New England Journal of Medicine 339:1609–1618.