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S.R. Cummings, MD, University of California-San Francisco and researchers in 25 countries gave RAL to over 5,000 osteoporotic women mainly to measure the risk for bone fractures. Dosing with 60 mg or 120 mg daily for about 2 years also led to a 72% reduction in breast cancer compared with 2,500 others on placebo. The investigators plan to continue the controlled trial to reach 5 years follow-up. RAL is currently approved for prevention of osteoporosis in postmenopausal women. This drug should not be taken by women who are or may become pregnant or with active or past history of venous thrombolic events, according to US labeling.

Background for study

RAL is a selective estrogen modulator (SERM) which increases bone density and improves lipid metabolism. This drug binds to estrogen receptors and regulates target genes by blocking estrogen in breast and uterine tissue. The trial protocol hypothesized that RAL would reduce the risk of bone fractures and developing breast or endometrial cancer in postmenopausal women with osteoporosis. Cummings limited the presentation to the results on cancer prevention.

Controlled trial methodology

For study entry, patients had to be postmenopausal, under 80 years of age, have a history of osteoporosis (spine fracture or spine density clearly below the normal for young white women), and be free of a history of prior breast or uterine cancer, or bleeding. The 7,705 qualified women were randomly assigned to have one third on placebo treatment and the rest to take RAL as 60 or 120 mg daily at 180 research centers.

About 50% of the subjects had optional mammography at year one and nearly all a mandatory examination at year two of study. Thirty percent of the women also had vaginal ultrasound testing. Biopsy examination followed in patients who had abnormal bleeding, an ultrasound test, or if endometrial thickness greater than 5 mm. A masked expert panel validated all observed pathologies.

Interim results of double-blind trial

At baseline, the treated and control groups were similar:

  • 96% white and 82% under the age of 60
  • 12% with a family history of breast cancer
  • 17% drank >3 alcoholic drinks/wk, a known risk factor

Over the study period (median, 33 mo), invasive breast cancer developed in 22 (0.85%) placebo- and 13 (0.24%) RAL-treated patients; the estimated relative risk (RR) was 0.26 (CI 0.13-0.52). The results in both RAL groups showed no real difference in response between 60 mg and 120 mg daily.

Four (0.16%) patients on placebo and another 4 (0.08%) treated women developed endometrial uterine cancer. Two of 4 patients in the RAL group were diagnosed for uterine cancer during the first month of treatment. Excluding both patients gave an RR of 0.13 (p=0.045).

Information on adverse drug events (ADEs) was not presented.

Invited discussion of reported data

C.K. Osborne, MD, University of Texas Health Sciences Center-San Antonio, found the RAL vs placebo trial yielded "exciting" results and established "a paradigm for targeted prevention approaches." Early benefits occurred but must be interpreted conservatively since the process of breast cancer evolution may take many years or decades to reach the clinical stage.

Further examination of the results led Osborne to ask:

  • Does RAL have only an early treatment effect? Will women with hereditary breast cancer susceptibility benefit?
  • What is the proper age to start RAL treatment? What is the optimal duration of therapy?
  • Over time, will more breast tumors become larger than 2 cm, have 4 or more positive nodes, or show estrogen receptor negativity?
  • Will RAL treatment affect the incidence of Alzheimer's disease?

Osborne does not recommend extrapolating the RAL trial results to the general population of women. The decision to initiate estrogen- replacement therapy, tamoxifen, or RAL requires careful thought and discussion of the benefits and risks with each patient.

Eugene A. Conrad

Presented at the American Society of Clinical Oncology (ASCO) Meeting, May 16-19, 1998
Copyright © 1998 Conrad Group Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / June 1998
Send Comments to: ConradNote@aol.com


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