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Key Words

Breast cancer, coronary heart disease, osteoporosis, raloxifene (Evista®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ³.)

Summary

The drug raloxifene (Evista®) did not prevent heart problems in postmenopausal women with, or at high risk for, coronary heart disease. The drug significantly reduced the risk of invasive breast cancer and spinal fractures, but also increased the incidence of blood clots and death from stroke.

Sources

Journal of the National Cancer Institute, June 18, 2008 (see the journal abstract ⁴)
J Natl Cancer Inst. 2008 Jun 18;100(12):854-61. Epub 2008 Jun 10)

New England Journal of Medicine, July 13, 2006 (see the journal abstract).
(N Engl J Med 2006 Jul 13;355(2):125-37)

Background

Recent large clinical trials have shown that the drug raloxifene, which was originally developed to help prevent osteoporosis, can also reduce the risk of breast cancer in postmenopausal women at high risk of the disease.

In the Multiple Outcomes of Raloxifene (MORE) trial, the drug lowered breast cancer incidence in postmenopausal women with osteoporosis by 72 percent over four years, compared to a placebo. The Study of Tamoxifen and Raloxifene (STAR) trial compared raloxifene to tamoxifen for the prevention of breast cancer in postmenopausal women at increased risk for breast cancer. Both tamoxifen and raloxifene reduced the risk of developing invasive breast cancer by about 50 percent (see the NCI press release about STAR) ⁵.

The Raloxifene Use for The Heart (RUTH) trial, described in this summary, was an international randomized clinical trial that was originally designed to determine whether raloxifene could reduce the risk of coronary heart disease in postmenopausal women who had coronary heart disease (CHD) or who were at high risk of CHD. (Coronary heart disease – damage to the coronary arteries that supply blood to the heart - is the most common form of heart disease.) When results from the MORE trial showed a reduction in breast-cancer risk with use of the drug, the RUTH team expanded their study to look at raloxifene’s effect on breast cancer risk.

The Study

Between June 1998 and August 2000, investigators from 26 countries enrolled 10,101 eligible women into the trial. Participating women were randomly assigned to receive either 60 milligrams of raloxifene a day (5,044 patients), or an identical placebo pill (5,057 patients).

Researchers checked on the women’s health status and compliance with their medication schedule twice a year. In addition, an electrocardiography (a test used to measure the condition of the heart) was performed at the beginning of the study, during year 2 and year 4 of follow-up, and during the last follow-up visit. Mammograms and clinical breast examinations were performed at the start and every two years during follow-up.

Patients’ cholesterol levels were measured at the beginning of the study, during year 1 and year 5 of follow-up, and during the last follow-up visit. Coronary events included death from a heart attack, from heart failure, or during heart surgery; a nonfatal heart attack; or hospitalization for other heart problems. Investigators recorded occurrences of coronary events; breast cancer; noncoronary events such as stroke and venous thromboembolism (blood clots in the cardiovascular system); bone fractures; and death. Participants voluntarily reported side effects when they attended checkups.

Results

In both the raloxifene and placebo groups, patients were followed for a median of 5.6 years. About 80 percent of patients in both groups completed the study, and about 70 percent in both groups took at least 70 percent of the assigned medication.

The number of women reporting side effects was not significantly different in the two groups, though more women in the raloxifene group stopped use of the study drug because of side effects.

Investigators did not see any significant differences between the two groups in the number of deaths from coronary causes, nonfatal heart attacks, or hospitalizations for an acute coronary syndrome. These results were unaffected by whether women already had CHD or were at increased risk for CHD.

Levels of low-density lipoprotein (‘bad’) cholesterol declined significantly and levels of high-density lipoprotein (‘good’) cholesterol increased significantly in the raloxifene group. However, these changes did not correspond to a protective effect on the heart.

During the followup period, 76 women in the placebo group were diagnosed with breast cancer compared with 52 in the raloxifene group. Raloxifene reduced the risk of invasive breast cancer by 44 percent overall; the incidence of estrogen-receptor positive breast cancers was reduced by 55 percent, but no reduction was seen in the incidence of estrogen-receptor negative breast cancers. The reduction in breast-cancer risk did not differ significantly between women at increased risk and women at normal risk of breast cancer. The reduction in breast cancer incidence was seen by the second year of treatment. The incidence of clinical vertebral fractures was reduced by 35 percent.

Fifty-nine women in the raloxifene group (1 percent), compared with 39 in the placebo group (0.7 percent) died from stroke, which translates into a statistically significant 49 percent higher risk on raloxifene. Similarly, though the absolute numbers were small, women on raloxifene were 44 percent more likely to suffer a noncoronary blood clot than those on placebo.

Comments

Notes Leslie Ford, M.D., associate director of the National Cancer Institute’s Division of Cancer Prevention: “Although raloxifene had no effect on coronary heart disease in this group of women at risk for heart disease, this analysis confirms the value of the drug in preventing bone loss and in reducing breast cancer risk in postmenopausal women.”

On the basis of laboratory studies that showed raloxifene enhanced bone density and lowered circulating blood cholesterol, the drug was tested both to prevent fractures from osteoporosis (the MORE trial) and to reduces CHD (the RUTH trial), although investigators believed the drug might also prevent breast cancer, comments V. Craig Jordan, Ph.D., Sc.D, ,in an editorial accompanying the updated published results. “It is now clear, based on clinical trials data, however, that raloxifene is not effective to reduce the risk of coronary artery disease,” Jordan writes.

Choosing preventive treatment for any individual patient “is about risks and benefits,” said Ford. “If you don’t have any risk factors for breast cancer, but you want prevent osteoporosis, you have a choice of raloxifene, which can reduce the risk of both conditions, or a bisphosphonate that will address bone loss only. There isn’t one pill that is going to address all of your needs. You need to consider your prior health history, and the reasons for treatment, before you decide to take one or the other.”

Glossary Terms

A drug or substance used to treat hypercalcemia (abnormally high blood calcium) and bone pain caused by some types of cancer. Forms of bisphosphonates are also used to treat osteoporosis and for bone imaging. Bisphosphonates inhibit a type of bone cell that breaks down bone. Also called diphosphonate.

An exam of the breast performed by a health care provider to check for lumps or other changes.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called a clinical study.

CAD. A disease in which there is a narrowing or blockage of the coronary arteries (blood vessels that carry blood and oxygen to the heart). Coronary artery disease is usually caused by atherosclerosis (a build up of fatty material and plaque inside the coronary arteries). The disease may cause chest pain, shortness of breath during exercise, and heart attacks. The risk of coronary artery disease is increased by having a family history of coronary artery disease before age 50, older age, smoking tobacco, high blood pressure, high cholesterol, diabetes, lack of exercise, and obesity. Also called CAD and coronary heart disease.

Describes cells that have a protein to which the hormone estrogen will bind. Cancer cells that are estrogen receptor positive need estrogen to grow, and may stop growing when treated with hormones that block estrogen from binding. Also called ER+.

Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer.

An x-ray of the breast.

A statistics term. The middle value in a set of measurements.

A condition that is marked by a decrease in bone mass and density, causing bones to become fragile.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

Having to do with the time after menopause. Menopause (“change of life”) is the time in a woman's life when menstrual periods stop permanently.

A drug used to reduce the risk of invasive breast cancer in postmenopausal women who are at a high risk of developing the disease or who have osteoporosis. It is also used to prevent and treat osteoporosis in postmenopausal women and is being studied in the prevention and treatment of other conditions. Raloxifene blocks the effects of the hormone estrogen in the breast and increases the amount of calcium in bone. It is a type of selective estrogen receptor modulator (SERM). Also called raloxifene hydrochloride and Evista.

In statistics, describes a mathematical measure of difference between groups. The difference is said to be significant if it is greater than what might be expected to happen by chance alone. Also called statistically significant.