European trials fail to confirm benefit of tamoxifen
The Royal Marsden Trial was one of 2 European trials that failed to replicate the BCPT results.10 This British study involved 2,471 healthy women between the ages of 30 and 70 who had a family history of breast cancer. The immediate follow-up was 70 months. No statistically significant decrease in breast cancer was found with tamoxifen use, compared with placebo.
One possibility for the discrepancy may be that eligibility for the Royal Marsden Trial was based predominantly on a strong family history of breast cancer. It also included a much larger proportion of women under age 50 (62%, compared with only 40% in the BCPT). Probably most importantly, 42% of the women received hormone replacement therapy (HRT) along with tamoxifen during the trial.
The Italian prevention study also failed to confirm the findings of the BCPT.11 Because it recruited participants from the general population, the overall risk of breast cancer was significantly lower than in the BCPT. Compliance rates in the Italian study were quite low: Approximately 26% of the subjects dropped out. Furthermore, the Italian trial included considerably fewer women over age 60 (12% versus 30% in the BCPT).
Raloxifene: Another cancer preventive?
Like tamoxifen, raloxifene is a SERM. It is a benzothiophene derivative; tamoxifen comes from the triphenylethylene family.
Like tamoxifen, raloxifene was originally investigated as a treatment for advanced breast cancer. Preclinical studies indicated that it had an antiproliferative effect on estrogen-receptor–positive mammary tumors and estrogen-receptor–positive human breast cancer cell lines.12 However, in the 1980s, a small phase II trial revealed that it had no further antitumor effects in postmenopausal women with advanced breast cancer in whom tamoxifen therapy had failed.13
Interest in raloxifene revived after tamoxifen’s neoplastic effects on the uteri of postmenopausal women became evident.14 As a SERM, raloxifene exhibits estrogen-agonist activity on bone remodeling and lipid metabolism. In December 1997, it won FDA approval for the prevention of osteoporosis in postmenopausal women. Its indication was extended to treatment in October 1999.
Studies found that raloxifene was similar to placebo in its effects on the endometrium of postmenopausal women.15 There were no differences in endometrial thickness, endoluminal masses, proliferation, or hyperplasia. This corroborated previous findings that raloxifene causes neither endometrial hyperplasia nor cancer and is not associated with vaginal bleeding or increased endometrial thickness (as measured by transvaginal ultrasound).
In addition, preclinical animal data suggest that, like tamoxifen, raloxifene has potent antiestrogen effects on breast tissue.12
The MORE trial involved 7,705 postmenopausal women up to age 80 with established osteoporosis who were randomized to receive raloxifene or placebo. Bone mineral density and fracture incidence were the primary endpoints; breast cancer was a secondary endpoint. At 4 years, raloxifene significantly reduced the incidence of all invasive breast cancers by 72%, compared with placebo (RR = 0.28; 95% CI, 0.17–0.46).16 It reduced the incidence of invasive estrogen-receptor–positive tumors by 84%, compared with placebo (RR = 0.16; 95% CI, 0.09–0.30), but had no effect on estrogen-receptor–negative tumors.
Because they block both initiation and promotion of breast cancer, aromatase inhibitors may be more effective than SERMs in preventing breast cancer.
The incidence of vaginal bleeding, breast pain, and endometrial cancer in the raloxifene group did not differ significantly from those of the placebo group. (Because women in the MORE trial were older and did not enter the study with an increased risk for breast cancer, these findings are not necessarily applicable to younger, high-risk women.)
Like tamoxifen, raloxifene slightly increased the risk of thromboembolic disease, including deep vein thrombosis. Pulmonary embolism developed in 1.1% of women in the raloxifene group, compared with 0.5% of subjects in the placebo group (P = .003).
Currently, there is no approved indication for raloxifene in premenopausal women. SERM compounds, which are structurally similar to clomiphene citrate, seem to have different effects in premenopausal and postmenopausal women, as tamoxifen did in the BCPT. Further study in the premenopausal population or with concomitant use of lowdose estrogen may be forthcoming.
Ongoing clinical trials
STAR. To directly compare the safety and efficacy of tamoxifen and raloxifene in reducing breast cancer risk among healthy women, the Study of Tamoxifen and Raloxifene (STAR) has been enrolling postmenopausal women 35 years of age or older who are at increased risk for breast cancer. This study began in 1999 and is expected to run for at least 7 years. It seeks to enroll 22,000 participants in its randomized, double-blind investigation. Participants will receive a daily dose of raloxifene (60 mg) or tamoxifen (20 mg).