The case for chemoprevention as a tool to avert breast cancer

The genesis of a drug with multiple benefits

Raloxifene is a benzothiophene derivative, unlike the triphenylethylene family from which tamoxifen is derived. Like tamoxifen, raloxifene was originally investigated as a treatment for advanced breast cancer.

Preclinical studies indicated that raloxifene had an antiproliferative effect on both estrogen-receptor–positive mammary tumors and estrogen-receptor–positive human breast cancer cell lines.⁹ In the 1980s, however, a small, phase-II trial revealed that raloxifene had no further antitumor effects in postmenopausal women with advanced breast cancer in whom tamoxifen had failed.¹⁰ After information surfaced about the neoplastic effect of tamoxifen on the uteri of postmenopausal women, interest in raloxifene revived.¹¹

Raloxifene has estrogen-agonistic activity on bone remodeling and lipid metabolism and was approved by the FDA for prevention of osteoporosis in postmenopausal women in December 1997. Its indication was extended to treatment of osteoporosis 2 years later.

Raloxifene appears to have no effect on the endometrium of postmenopausal women, compared with placebo. In a 12-month comparative trial, there was no difference in endometrial thickness, endoluminal masses, proliferation, or hyperplasia between the raloxifene and placebo groups.¹² This finding corroborates earlier evidence that raloxifene does not cause endometrial hyperplasia or cancer and is not associated with vaginal bleeding or increased endometrial thickness, as measured by transvaginal ultrasonography.

A big difference between raloxifene and tamoxifen, therefore, is their varying effect on the uterus of postmenopausal women.

Additional clinical trials confirm anticancer action of raloxifene

Preclinical data in animal models suggested that, like tamoxifen, raloxifene has potent antiestrogenic effects on breast tissue.⁹ The MORE trial involved 7,705 postmenopausal women up to 80 years old who had established osteoporosis.¹³ In that trial, participants were randomized to raloxifene or placebo. Bone mineral density (BMD) and fracture incidence were the primary endpoints; breast cancer was a secondary endpoint.

Over the 4 years of the trial, raloxifene significantly reduced the incidence of all invasive breast cancers by 72%, compared with placebo (RR, 0.28; 95% CI, 0.17–0.46). Raloxifene also significantly 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. The incidence of vaginal bleeding, breast pain, and endometrial cancer in the raloxifene group did not differ significantly from that of the placebo group.

Like tamoxifen, raloxifene appeared to be associated with an increased risk of thromboembolic disease, including DVT and pulmonary embolism, which developed in 1.1% of women taking raloxifene, compared with 0.5% of women in the placebo group (P=.003).

In a 4-year continuation of the MORE trial, known as the Continuing Outcomes Relevant to Evista, or CORE, trial, 5,231 women were randomized to continue raloxifene or placebo.¹⁴ Over the 8 years of the combined trials, the incidence of invasive breast cancer was reduced by 66% in the raloxifene group (RR, 0.34; 95% CI, 0.22–0.50). The 8-year data are extremely clinically relevant, in that raloxifene has no time limit, whereas tamoxifen is usually prescribed for no longer than 5 years.

Raloxifene is not approved for use in premenopausal women. SERM compounds, which are structurally similar to clomiphene citrate, seem to have different effects in premenopausal and postmenopausal women, as evidenced by tamoxifen’s differing effects by age in the BCPT.

Other investigations of raloxifene confirm its value in high-risk women

To compare the clinical safety and efficacy of tamoxifen and raloxifene in reducing the risk of breast cancer among healthy women, the Study of Tamoxifen and Raloxifene (STAR) was initiated in 1999.¹⁵ In that trial, 19,747 postmenopausal women older than 35 years were blindly assigned to raloxifene 60 mg or tamoxifen 20 mg daily.

Baseline characteristics of subjects in STAR are summarized in TABLE 2 . Mean age was 58.5 years. All women had a 5-year risk of developing breast cancer that exceeded 1.66%, according to the Gail model. The average Gail score was 4.03% (standard deviation, ±2.17%). Because it would have been unethical to subject high-risk women to a placebo group in light of the findings of the BCPT, there was no placebo control.

TABLE 2

Baseline characteristics of women
in the Study of Tamoxifen and Raloxifene (STAR) trial

Here are noteworthy findings of the STAR trial:

• 163 cases of invasive breast cancer occurred in the tamoxifen group, compared with 168 among women taking raloxifene (RR, 1.02; 95% CI, 0.82–1.28).
• 36 cases of uterine cancer occurred in the tamoxifen group, compared with 23 among women taking raloxifene (RR, 0.62; 95% CI, 0.35–1.08). Earlier studies had shown a marked difference in the rate of uterine cancer between these agents. Although the difference here is not statistically significant, uterine cancer was not an endpoint of the study; nor was the study powered to explore this difference.
• The number of hysterectomies among women who were diagnosed with endometrial hyperplasia with or without atypia was, proportionally, significantly higher among women taking tamoxifen ( TABLE 3 ).
• No difference between groups was found for other invasive cancers, ischemic heart events, or stroke.
• Thromboembolic events occurred less frequently in the raloxifene group (RR, 0.70; 95% CI, 0.54–0.91). However, both raloxifene and tamoxifen have consistently been associated with a twofold to threefold increase in the risk of thromboembolic events, compared with placebo.
• Vasomotor symptoms and leg cramps increased in frequency and severity among women in both groups of the trial. These symptoms appear to be less common and less severe among women who are older and more remote from the onset of menopause.