Raloxifene Equals Tamoxifen in Reducing Breast Cancer Risk

BETHESDA, Maryland—Raloxifene (Evista, Eli Lilly) has proven as effective as tamoxifen in reducing the risk of invasive breast cancer in postmenopausal women who are at increased risk of the disease. Initial findings from the Study of Tamoxifen and Raloxifene (STAR) showed that both drugs reduced breast cancer risk by about 50% but that patients in the raloxifene arm had 36% fewer uterine cancers and 29% fewer blood clots than those on tamoxifen.

"These results demonstrate that raloxifene is an effective alternative to tamoxifen for preventing invasive breast cancer, and with fewer life-threatening side effects," D. Lawrence Wickerham, MD, told ONI in an interview. Dr. Wickerham serves as the STAR protocol officer and associate chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which coordinated the National Cancer Institute-supported trial.

In 1998, results from the Breast Cancer Prevention Trial, a study of more than 13,000 women, showed that tamoxifen could cut the risk of breast cancer by half in both pre- and postmenopausal women at elevated risk of the disease. However, this preventive treatment carried with it a low but real risk of potentially fatal adverse events, particularly stroke and uterine cancer.

By then, clinical reports suggested that raloxifene, a drug now approved for use in preventing and treating osteoporosis in postmenopausal women, could also reduce the risk of developing breast cancer, and with fewer side effects. As a result, NCI decided to sponsor a trial to compare the two drugs.

STAR is a prospective, randomized, double-blind study that enrolled its first patients in July 1999, and eventually accrued 19,747 women at more than 400 sites in the United States, Puerto Rico, and Canada. Its protocol required participants to be postmenopausal, at least age 35, and have an increased risk of breast cancer as determined by their age, family history of breast cancer, personal medical history, age of first menstrual period, and age at first live birth. Exclusion criteria included a history of blood clots and other disorders that increase the risk of stroke.

Participants were randomized to receive 60 mg of raloxifene or 20 mg of tamoxifen daily for 5 years. Results were based on data from the 19,471 women for whom researchers had complete study information—9,745 in the raloxifene arm and 9,726 in the tamoxifen group. Patient follow-up was a mean of 4 years. The STAR findings were released by NSABP and NCI officials during a teleconference with members of the media.

The results showed that a statistically equivalent number of invasive breast cancers developed in the two groups of women—167 in the raloxifene arm and 163 in the tamoxifen group. Previous studies have shown that tamoxifen reduces by half the incidence of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS). However, the women receiving raloxifene did not reap the same benefit: 57 women in the tamoxifen group developed LCIS or DCIS vs 81 in the raloxifene arm.

More than 50% of the women in the study had undergone a hysterectomy and, thus, had no risk of uterine cancer. The women who retained their uterus numbered 4,732 in the tamoxifen group and 4,712 in the raloxifene arm. Of these at-risk women, 36 of the tamoxifen-treated participants and 23 of those assigned to raloxifene developed a uterine cancer, primarily endometrial cancer. "The uterine cancer difference came close to significance," Dr. Wickerham said. In addition, 84 women receiving tamoxifen and 14 randomized to raloxifene developed endometrial hyperplasia.

Raloxifene-treated women had 29% fewer clotting problems: 87 women receiving tamoxifen suffered deep-vein thrombosis and 54 had pulmonary embolisms, compared, respectively, to 65 and 35 such clots in the raloxifene group. Statistically, the clotting data varied from significant to nearly significant.

The data suggest that raloxifene, unlike tamoxifen, does not put women at increased risk of developing a cataract.

Strokes, Heart Attacks Equivalent

Strokes and stroke-related death proved statistically equivalent in both groups, with 53 strokes (6 deaths) in the tamoxifen arm and 51 strokes (4 deaths) among the women receiving raloxifene. Heart attacks also were statistically equivalent in both study arms.

STAR researchers found no significant difference in bone fractures between the two groups and no significant differences in the more common side effects associated with the two drugs, including hot flashes and vaginal discharges. Quality of life, as reported by the participants, was the same in both arms.

With the study unblinded, women in the tamoxifen arm who have not completed their 5-year treatment have the option of remaining on the drug or switching to raloxifene for the rest of their time in the study. STAR scientists will continue to follow the patients annually once they complete their 5 years of treatment, including annual mammograms. "The protective benefits of tamoxifen do not stop with the last dose of the drug but are present out to 15 years, which is as long as we have followed patients," Dr. Wickerham said. "The same is probably true for raloxifene."

STAR researchers will present additional data from the study at the 2006 Annual Meeting of the American Society of Clinical Oncology in Atlanta.