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Adjuvant Tamoxifen Reduces Breast Cancer Incidence But Risks Still Unclear

Evidence from a large, five-year international trial shows that adjuvant tamoxifen reduces the risk of breast cancer in high-risk women, but questions remain as to whether the benefits outweigh the risks.

"Further long-term follow-up to study breast-cancer incidence and mortality, other causes of death, and side effects in the current trials remains essential," declares Dr. Jan Cuzick, director of the International Breast Cancer Intervention Study (IBIS-I), at the Trials Center, Cancer UK, London, England. The next trial by the investigators, IBIS-II, will consider using an aromatase inhibitor as an option.

The IBIS-1 trial is a double-blind, placebo-controlled, randomised study of tamoxifen, 20 mg/day for five years, in 7,144 women between the ages of 35 and 70 years, who were at increased risk of breast cancer. It is being carried out by clinicians in Britain and other European countries, Australia and New Zealand.

The primary outcome measure is the frequency of breast cancer, including ductal carcinoma in situ.

Clinicians point out that three earlier studies produced mixed results. A 50 percent decrease in breast-cancer incidence was observed in a North American trial of adjuvant tamoxifen, but little or no reduction was seen in two European trials. "The possible reasons for the differences in results have been the subject of much discussion, but no clear explanation is available," say the researchers. Results from the three trials are statistically compatible with a 30 to 40 percent decrease in incidence.

In a median follow-up of 50 months, Dr. Cuzick and colleagues found that 69 breast cancers had been diagnosed in 3, 578 women in the tamoxifen group, and 101 breast cancers among 3,566 women in the placebo group (p=0.013). These reductions were not affected by age of the women, the degree of their risks, or whether or not they used hormone replacement therapy.

Endometrial cancer was non-significantly increased: 11 cases among the women taking tamoxifen and five among those on placebo (p=0.2). All cases were localised (stage 1) and curable by hysterectomy.

Thromboembolic events were significantly increased in the tamoxifen group, especially after surgery: 43 cases compared with 17 among those on placebo (p=0.001).

In addition, there was a significant excess of deaths from all causes in the tamoxifen group: 25 deaths compared with 11 among women on placebo. The investigators said that the increased risk of thromboembolic complications could contribute to the higher all-causes-mortality rate among women given tamoxifen.

Although tamoxifen is unquestionably valuable in the adjuvant setting, the clinicians said, "some of its estrogen-agonist properties restrict its ultimate usefulness" for both efficacy and side effects. "Early results show that anastrozole is more effective than tamoxifen in reducing recurrence (by about 25 percent in estrogen receptor-positive tumors), and this drug seems to be even more promising in reducing the risk of new contralateral tumors (58 percent reduction compared with tamoxifen)."

The agonist properties of tamoxifen account for its main side effects of thromboembolic events and endometrial cancer, which do not occur with aromatase inhibitors.

However, Dr Cuzick and colleagues conclude that new issues in relation to bone loss and other potential effects of long-term estrogen deprivation might arise. "The use of an aromatase inhibitor in the preventive setting is attractive and will be considered as an option in the forthcoming IBIS-II trial."
Lancet 2002; 360: 817-24

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