Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Raloxifene reduced the incidence of breast cancer in postmenopausal women with osteoporosis

ACP J Club. 1999 Nov-Dec;131:58. doi:10.7326/ACPJC-1999-131-3-058


Source Citation

Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. Results from the MORE randomized trial. JAMA. 1999 Jun 16;281:2189-97.


Abstract

Question

In postmenopausal women with osteoporosis, is raloxifene safe and effective for reducing the incidence of breast cancer?

Design

Randomized, triple-blind, placebo-controlled trial with 3-year follow-up (Multiple Outcomes of Raloxifene Evaluation [MORE] study).

Setting

180 clinical centers in 25 countries.

Participants

22 379 postmenopausal women were screened, and 7705 were studied (mean age 67 y, 96% white, 12% with a family history of breast cancer). All women had confirmed osteoporosis and were postmenopausal for ≥ 2 years. Exclusion criteria were known, suspected, or history of breast cancer; endometrial or other cancer; abnormal uterine bleeding; history of stroke or venous thromboembolism (VTE); secondary causes of osteoporosis; other types of bone disease; current or recent use of estrogens, progestins, androgens, or systemic corticosteroids; or consumption of > 4 alcoholic drinks/d.

Interventions

Women received calcium, 500 mg/d, and cholecalciferol, 400 to 600 IU/d and were allocated to raloxifene, 120 mg/d (n = 2572); raloxifene, 60 mg/d (n = 2557); or placebo (n = 2576).

Main outcome measures

Confirmed breast cancer and adverse effects, including VTE and endometrial cancer. Breast cancer screening was mandatory at 2 and 3 years.

Main results

All women were included in the intention-to-treat analysis, and data from the 2 raloxifene groups were combined. Compared with the placebo group, women in the raloxifene groups had a lower incidence of breast cancer (P < 0.001) (Table); higher rates of influenza-like syndromes, hot flashes, leg cramps, endometrial cavity fluid, peripheral edema, hypercholesterolemia, diabetes, VTE (Table), and deep venous thrombosis and lower rates of hypertension, hematuria, and bradycardia (P < 0.01 for all comparisons). Rates of endometrial cancer were similar for all groups (P > 0.2).

Conclusion

Raloxifene reduced the incidence of breast cancer in postmenopausal women with osteoporosis at 3 years.

Source of funding: Eli Lilly & Co.

For correspondence: Dr. S.R. Cummings, Prevention Sciences Group, Suite 600, 74 New Montgomery, San Francisco, CA 94105, USA. FAX 415-476-7964.


Table. Raloxifene vs placebo to prevent breast cancer in postmenopausal women with osteoporosis at mean follow-up of 40 months*

Outcomes Raloxifene Placebo RRR (95% CI) NNT (CI)
Invasive breast cancer 0.25% 1.05% 76% (53 to 87) 126 (78 to 234)
All breast cancer 0.43% 1.24% 65% (41 to 80) 123 (74 to 253)
RRI (CI) NNH (CI)
Venous thromboembolism 0.96% 0.31% 208% (48 to 538) 155 (101 to 363)

*Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article.


Commentary

Tamoxifen has recently been reported to reduce the risk for breast cancer (1, 2), and a similar finding is now reported for raloxifene. Cummings and colleagues are to be commended for completing a well-designed study; however, few adverse events and short follow-up make the findings preliminary. Although breast cancer was a secondary end point, the results are impressive and show a clear reduction in incidence.

Raloxifene offers no advantage over tamoxifen in terms of risk for VTE and troublesome side effects, such as hot flashes. Unlike tamoxifen, raloxifene does not seem to increase the risk for endometrial cancer; however, the endometrial effects seen with raloxifene are cause for concern. Although raloxifene is a selective estrogen-receptor modulator, long-term use may be associated with higher rates of adverse events. Confirmatory trials with long-term follow-up and the primary end point of reduction in risk for breast cancer must be done, and safety must be established.

Many issues remain unresolved. Is raloxifene truly better than tamoxifen? What is the optimum duration of use of these agents? At what age should therapy be started? Will survival be improved? Which women will benefit the most? The reduction in breast cancer with raloxifene is primarily caused by a decrease in estrogen-receptor positive cases, and we are currently unable to identify women who are at risk for this specific type of breast cancer. In addition, results may not be applicable to women who are at risk for hereditary breast cancer, which tends to occur at a younger age and may be more likely to be estrogen-receptor negative.

Edmond Chouinard, MD
Hamilton Regional Cancer CentreHamilton, Ontario, Canada


References

1. Chlebowski RT, Collyar DE, Somerfield MR, Pfister DG. American Society of Clinical Oncology Technology Assessment on Breast Cancer Risk Reduction Strategies: tamoxifen and raloxifene. J Clin Oncol.1999;17:1939-55.

2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-88.