Friday, October 12, 2007

Tamoxifen and raloxifene for the prevention of breast cancer

INTRODUCTION — Approximately 210,000 women in the United States are newly diagnosed with breast cancer each year. Certain risk factors may increase the likelihood that a woman will develop breast cancer, including advancing age and a strong family history of breast cancer, among others. Based upon a careful risk assessment, healthcare providers sometimes recommend therapy with one of two medications (tamoxifen or raloxifene) to reduce the chance of developing breast cancer for women at increased risk. The term chemoprevention is applied to the use of a medication to prevent cancer from developing in a high-risk individual. (See "Patient information: Risk factors for breast cancer").

The following is a discussion of studies evaluating the effectiveness of both tamoxifen and raloxifene for breast cancer chemoprevention, possible adverse effects, and information about which women should consider taking one of these agents.

HOW DO TAMOXIFEN AND RALOXIFENE WORK? — Both tamoxifen and raloxifene are members of a drug class called Selective Estrogen Receptor Modulators (SERMs). The use of SERMs to prevent breast cancer in high-risk women came about because of the success of tamoxifen in reducing the occurrence of new cancers in the opposite breast of women who had early breast cancer. This finding suggested that tamoxifen might play a role in the prevention of breast cancer in women who have not yet developed breast cancer.

Drugs like SERMs work as breast cancer chemopreventive agents because they are able to interfere with the effect of the female hormone estrogen on certain tissues, such as the breast. Besides influencing the growth of breast tissue, estrogen performs a variety of other functions in a woman's body, including sexual development, proper functioning of the reproductive system, and maintaining bone strength.

Many cells in the body, especially within estrogen-sensitive tissues like the breast, contain specialized proteins that bind estrogen. These proteins are known as estrogen receptors (ERs). Both normal cells and cancerous cells within breast tissue may contain ERs; the binding of estrogen to these ERs stimulates the cells to grow and divide.

SERMs such as tamoxifen and raloxifene do not just prevent estrogen from interacting with its receptor. SERMS actually interact with ERs in different ways in different tissues of the body. Depending on the specific tissue, the effect can either be to block the effects of estrogen (called antiestrogenic effects, such as occurs in the breast tissue), or to mimic the effects of estrogen (called estrogenic effects). Thus, in the same person, a SERM such as tamoxifen can be antiestrogenic in some tissues and estrogenic in others (show figure 1). These effects can be both beneficial and detrimental: Both tamoxifen and raloxifene have antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in women with breast cancer. In women at high risk of breast cancer, both tamoxifen and raloxifene can prevent new ER positive breast cancers. Tamoxifen and raloxifene also have antiestrogenic activity on certain parts of the brain. This can lead to many of the menopausal symptoms (eg, hot flashes, sweating, insomnia) that occur in 30 to 40 percent of women who take them. Tamoxifen and raloxifene are estrogenic in the bones of postmenopausal women. They can prevent loss of bone mass and decrease the risk of developing bone fractures of the spine. (See "Patient information: Osteoporosis causes, diagnosis, and screening" and see "Patient information: Osteoporosis prevention and treatment").

However, in premenopausal women, tamoxifen has an antiestrogenic effect on bones and can cause slight bone loss, which is generally reversible when the drug is stopped (if the woman is still menstruating). Tamoxifen and raloxifene are estrogenic in the liver, and they increase the liver's production of blood-clotting proteins. This results in a slight increase in the risk of stroke, particularly in women who are at high risk for these events (ie, cigarette smokers, those with a past history of blood clots). Higher levels of clotting proteins also increase the risk of blood clots in the major veins of the leg (deep vein thrombosis) and migration of such a blood clot to the lungs (pulmonary embolus). The risk may be slightly lower with raloxifene compared with tamoxifen. (See "Patient information: Venous thrombosis"). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). Although most of the conditions that result from the growth of endometrial tissue are benign (eg, thickening of the lining of the uterus, or polyps), the risk of cancer of the uterus is increased by two- to threefold in women taking tamoxifen. Tamoxifen therapy may cause other bothersome side effects, including vaginal discharge and uterine bleeding.

In contrast, raloxifene is antiestrogenic in the endometrium, and does not appear to increase the risk of uterine cancer.


Tamoxifen — One American and three European research studies have examined the effectiveness of tamoxifen for the prevention of breast cancer. Overall, the evidence from these studies suggests that tamoxifen can prevent hormonally responsive (ie, ER-positive) breast cancers from developing in women at risk for the disease.

The largest trial examining the benefit of tamoxifen, known as the NSABP P-1 study, included over 13,000 American women age 35 years and older who were at increased risk for breast cancer because of their age, family history, or personal history of breast disease.

The women who participated were randomly assigned to tamoxifen at a dose of 20 milligrams (mg) per day or an inactive substance (placebo). The study was stopped early when researchers determined that there was a 50 percent decrease in the risk of developing breast cancer in women who took tamoxifen [1].

Despite the evidence that it reduces the risk of developing breast cancer in high-risk women, tamoxifen has not been widely accepted for chemoprevention largely because of the lack of evidence that survival is improved in women who receive tamoxifen as a chemopreventive agent, and a small risk of serious adverse events, including uterine cancer and blood clots in the legs or lungs.

Raloxifene — Raloxifene is currently used for the prevention and treatment of osteoporosis in postmenopausal women. Several studies suggest that in postmenopausal women at high risk of developing breast cancer, raloxifene can reduce the risk of developing an invasive hormonally-responsive (ER positive) breast cancer.

Raloxifene was directly compared to tamoxifen in a large trial involving postmenopausal women at high risk of breast cancer (called the Study of Tamoxifen and Raloxifene, or STAR trial). Participants were postmenopausal women over the age of 35 with a risk of breast cancer of at least 1.66, as determined by the Gail model, or a prior history of a precancerous breast condition, lobular carcinoma in situ (LCIS). Both tamoxifen and raloxifene were equally effective at preventing invasive breast cancer but raloxifene had less effect on the uterus and lower risk of blood clots than tamoxifen [2]. However, raloxifene has only been tested in postmenopausal women; its benefit in premenopausal women is unknown.

PRECAUTIONS — Tamoxifen and raloxifene are not recommended for some women, including those who: Have a history of deep vein thrombosis or pulmonary embolism Require anticoagulant or blood thinning medications Smoke Are pregnant, planning on becoming pregnant, or breastfeeding (tamoxifen may cause birth defects if taken during pregnancy)

Women who use tamoxifen prior to menopause should use a non-hormonal method of birth control (such as condoms and a diaphragm), since oral contraceptives or other hormonal methods may alter the effectiveness of tamoxifen. A woman should immediately notify her doctor if she becomes pregnant while on tamoxifen. (See "Patient information: Contraception").

Women who use tamoxifen or raloxifene should be closely monitored by their healthcare provider. In particular, women should: Have an annual gynecologic examination, including a breast examination and, if recommended, a yearly mammogram and Pap smear (screening of the cervix for cancerous or precancerous cells). Any woman who finds a new breast lump should speak with her health care provider about the need for diagnostic testing (mammogram, ultrasound, biopsy). Immediately report any abnormal gynecologic symptoms, such as menstrual irregularities, abnormal vaginal bleeding or spotting, staining, or pelvic pressure or pain. (See "Patient information: Abnormal uterine bleeding"). Immediate medical care is needed if signs or symptoms of a blood clot develop, such as calf tenderness, swelling, pain, or severe, unexplained breathlessness.

AROMATASE INHIBITORS — Aromatase inhibitors such as anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) are often used to treat women with hormone responsive breast cancer. Although data are not yet available, these agents are currently being studied in several trials for prevention of breast cancer.


Who should consider chemoprevention? — We suggest chemoprevention with a SERM in premenopausal and postmenopausal women who meet the definition of high risk for breast cancer. At present, this includes women with a history of a precancerous breast condition called lobular carcinoma in situ (LCIS) and those who have a calculated five-year risk of developing breast cancer of 1.66 percent or higher, according to a system called the Gail model. The Gail model uses a woman's current age; age at menarche; age at first live birth; the number of first degree relatives with a history of breast cancer; and the number and pathologic findings of any breast biopsies to estimate the probability of breast cancer over time.

A computer program to calculate an individual woman's risk is available at 1-800-4CANCER, or online at [3]. This risk assessment tool was developed for health professionals; patients who use it on their own should speak with their clinician for help interpreting the results. In addition, the presence of breast cancer risk factors does not mean that cancer is inevitable. Many women with risk factors never develop breast cancer.

An important issue is that these models do not consider the risk of cancer associated with inherited breast cancer-predisposing genes such as BRCA1 and BRCA2. Preliminary data suggest that there is benefit of tamoxifen for women with these mutations, at least in the reduction of breast cancer in the opposite breast of women with a history of breast cancer. (See "Patient information: Genetic testing for breast and ovarian cancer").

In general, the following women are candidates for tamoxifen or raloxifene: All women who are older than 60 years Postmenopausal women who are between 35 and 59 and who have an increased risk of breast cancer of at least 1.66 (as determined by the Gail model) Postmenopausal women who are 35 or older and have a history of LCIS

Premenopausal women at high risk of developing breast cancer who wish to use a medication to reduce their risk should consider tamoxifen because there are no data about the safety of raloxifene in premenopausal women.

The optimal duration of tamoxifen or raloxifene therapy for the primary prevention of breast cancer is not known. Based upon studies in women with breast cancer, the current recommendation is five years.

Tamoxifen or raloxifene?

Compared to tamoxifen, raloxifene is associated with a significantly lower risk of cataracts and blood clots in the legs and lungs but more muscle and bone pain, pain with sexual intercourse, and weight gain.

Raloxifene probably does not increase the risk of uterine cancers. In addition, other gynecologic problems such as uterine bleeding and need for a hysterectomy, hot flashes, and urinary incontinence problems are less common with raloxifene.

Raloxifene is currently approved for the prevention and treatment of osteoporosis, but not yet for breast cancer prevention. However, raloxifene is being used more frequently for chemoprevention in postmenopausal women due to the lower risk of some of the most severe side effects associated with tamoxifen. At present, raloxifene is not used for breast cancer chemoprevention in premenopausal women because of the lack of data regarding safety in this population.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site ( Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information

Web site of the American Society of Clinical Oncology
National Comprehensive Cancer Network

National Cancer Institute

American Cancer Society

Susan G. Komen Breast Cancer Foundation



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