Tamoxifen and raloxifene: Dealing with the side effects

Key Points

Carcinoma of the breast, either ductal or lobular, is not only the most frequently diagnosed cancer in women in the United States, affecting more than 200,000 women each year;¹ it's also the second most common cause of female cancer death (after lung cancer).

While the overall lifetime risk of breast cancer is one in seven, the risk increases with age. For women under age 50 the risk is only one in 50, while one in three of all breast cancers occur in women over age 75. For women between 50 and 69, routine mammography screening reduces mortality and improves overall prognosis.

The mainstay of treatment for early-stage cancer is surgery with adjuvant chemotherapy or hormonal therapy-or both. The goals of treatment are to improve survival and to prevent local or regional recurrence. Once the cancer has metastasized, however, the main treatment goals are to improve survival, to delay progression, and to maximize quality of life.

Instead, most women at high risk for breast cancer choose chemoprevention with selective estrogen receptor modulators (SERMs)-now referred to by the FDA as "estrogen agonist-antagonists"-the option that has also been the most successful.

Clinical trials evaluating SERMs include the National Surgical Adjuvant Breast and Bowel Project, Breast Cancer Prevention Trial (NSABP P-1) (n=13,388), the Multiple Outcomes of Raloxifene Evaluation (MORE) trial (n=7,705), and the Study of Tamoxifen and Raloxifene (STAR) trial (n=19,000).

The NSABP P-1 trial led to the FDA approval of tamoxifen to reduce risk of breast cancer. NSABP tested the effect of tamoxifen versus placebo on the incidence of breast cancer in high-risk women. Researchers observed significant gynecologic side effects of tamoxifen in the trial: hot flashes, vaginal discharge, and a threefold increased risk of uterine cancer.

The MORE trial resulted in the FDA approval of raloxifene for treatment of osteoporosis in postmenopausal women. The trial's secondary end point, however, was the reduction of breast cancer incidence. Although raloxifene did not seem to raise the risk of uterine cancer, it was linked to gynecologic symptoms, including vaginal atrophy and hot flashes.

The RUTH (Raloxifene Use for The Heart) trial was an international trial of 10,101 women that measured the occurrences of coronary events, breast cancer, and thrombotic events. The results showed that raloxifene reduced the risk of estrogen-receptor positive invasive breast cancer by 55%, compared to placebo. Raloxifene was approved by the FDA in September 2007 to prevent invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for developing invasive breast cancer.⁴

The STAR trial was launched by the NCI and the NSABP group to compare tamoxifen and raloxifene for preventing breast cancer in high-risk postmenopausal women. Secondary end points of the trial, in which more than 19,000 women enrolled, included endometrial cancer, ischemic heart disease, bone fractures, and quality of life. This trial showed that women taking raloxifene had a markedly lower risk of endometrial cancer than women taking tamoxifen, as well as fewer hot flashes and less vaginal discharge and bleeding.⁵

Our focus here is to discuss indications for, the gynecologic side effects associated with, and the management of, the two most commonly prescribed SERMs, tamoxifen and raloxifene. (Although in addition to SERMs, aromatase inhibitors and gonadotropin-releasing hormone agonists have significantly decreased breast cancer incidence, with fewer side effects, they are less commonly prescribed-and beyond the scope of this article. And space limitations permit us to only briefly mention the many other drugs being investigated, such as retinoids, selective COX inhibitors, and tyrosine kinase inhibitors, for ER-negative cancers.)