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Tamoxifen May Have a True Preventive Effect in Breast Cancer

Zosia Chustecka

February 22, 2007 – Long-term data showing that tamoxifen's effect of reducing the risk for breast cancer persists even after the drug is stopped have now been published in the February 21 issue of the Journal of the National Cancer Institute.

The latest results come from an analysis of the International Breast Cancer Intervention Study (IBIS-1), at a median follow-up of 8 years, and the Royal Marsden trial, at a median follow-up of 13 years. These data were presented at the San Antonio Breast Cancer Symposium in December 2006 and were reported by Medscape at that time.

Now, an editorial accompanying the publication of the studies says, "The long-term results of these 2 important trials reinforce the notion that tamoxifen is effective with an acceptable safety profile in reducing the risks of — and perhaps truly preventing — estrogen receptor [ER]–positive breast cancer in high-risk individuals."

Readdress Negative Perception of Tamoxifen

"We are now in a position to readdress the general negative perception of tamoxifen for standard breast cancer prevention," write the editorialists, Umberto Veronesi, MD, and colleagues from the European Institute of Oncology, in Milan, Italy.

These latest results from both studies suggest a "true preventive effect and not merely a transient risk reduction," the editorial comments. The IBIS-1 study showed a significant 29% reduction in breast cancer, and the benefit persisted even when the drug was stopped after 5 years. "Importantly, their data reveal a greater benefit of tamoxifen on ER-positive disease in the follow-up period and an appreciable tapering of adverse events after the active treatment period, such that the risk/benefit ratio improved," the editorialists note. In the Royal Marsden trial, the reduction in ER-positive disease was not readily apparent in the 8-year treatment period but became statistically significant with longer follow-up. Neither trial showed an effect on ER-negative breast cancer.

These results support previous evidence, coming from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1, conducted n the United States, and from a meta-analysis of adjuvant trials (Early Breast Cancer Trialists' Collaborative Group. Lancet. 2005;365:1687–1717), which suggests that the preventive effect is "durable — and possibly permanent," the editorialists comment. The effect "extends well beyond treatment cessation" — eg, 10 years in the meta-analysis.

Reassuring Picture of Safety

"Both studies paint a reassuring picture in terms of safety," the editorialists continue. Endometrial cancer was statistically significant in the IBIS-1 trial only during the active treatment period (12 cases with tamoxifen vs 3 with placebo; P = .02) but not overall (17 vs 11 cases) and was of borderline statistical significance in the Royal Marsden trial (13 vs 5 cases; P = .06). Similarly, venous thromboembolic events were doubled but statistically significant only in the active treatment phase in the IBIS-1 study, and there was no excess of cerebrovascular or cardiac events in either study. Surprisingly, there was no effect on bone fractures, the editorialists comment.

However, mortality has not been reduced by tamoxifen in any individual study, they point out. "It is reasonable to assume that the prevention of ER-positive breast cancers, which tend to have a good prognosis, does not translate into a substantial mortality reduction up to 10 years," they write. Longer-term follow-up is needed, but the current evidence of a 40% durable reduction of ER breast cancer is "still very important" in terms of a reduction in clinical and psychological morbidity and possibly also in terms of cost savings, they add.

Little Appeal Because of Poor Commercial Interest?

"Tamoxifen is a telling example of an effective agent with an unprecedented body of clinical evidence that has thus far had little appeal in the prevention setting, mainly because of its poor commercial interest (the drug is cheap and off patent)," the editorialists assert.

Other, newer drugs have recently been attracting publicity for the prevention of breast cancer. For example, raloxifene (Evista, Eli Lilly) has been proposed as a better-tolerated option to tamoxifen on the basis of results from the Study of Tamoxifen and Raloxifene (STAR). At the same time, the aromatase inhibitors (AIs) are being investigated in clinical trials both as an alternative to tamoxifen and as follow-on therapy to tamoxifen (the switching approach).

"The concept of the tamoxifen-AI switch has gained ground and is being aggressively investigated, with 1 trial already achieving favorable results on overall survival," the editorial comments. However, it also points out that in the STAR trial, raloxifene was less effective than tamoxifen at reducing ductal carcinoma in situ, and the participants of this trial need to be followed longer to discern whether raloxifene is truly equally effective.

The editorial concludes that the results of the IBIS-1 and Royal Marsden trials, together with the findings from the NSABP P-1 and STAR trials, convincingly move tamoxifen beyond the proof-of-principle stage and "underscore its worth as a standard viable option for preventing ER-positive breast cancer in high-risk women."

J Natl Cancer Inst. 2007;99:258–260, 272–282, 283–290.