Breast cancer and the postmenopausal woman

Alternatives to tamoxifen

Several other pharmacologic agents that affect reproductive hormones or their actions are being examined to reduce the risk of breast cancer. While raloxifene’s only approved indication is for the treatment of osteoporosis, secondary data analysis from the Multiple Outcomes of Raloxifene Evaluation (MORE) clinical trial showed a 76% reduction in the frequency of breast cancer in the raloxifene group. The analysis was criticized because the study was never designed as a breast cancer prevention study. Participants were not randomized based on their breast cancer risk, so it is unknown if the placebo and raloxifene groups had the same average risk. Also, the study population was at high risk for osteoporosis, and some research shows that such women have a lower overall risk of breast cancer. Since the follow-up period is now only 4 years, the question of suppression of growth versus true prophylaxis awaits resolution. The data are powerful evidence, however, of an anti-breast cancer effect of raloxifene.

The Study of Tamoxifen and Raloxifene (STAR) trial, currently enrolling participants, is aimed at clarifying the benefits of raloxifene. This will be the first breast cancer prevention trial to incorporate an active agent (tamoxifen instead of placebo) as the standard of care. Two additional ongoing trials that will add more raloxifene data are Raloxifene Use for The Heart (RUTH) and Continuing Outcomes Relevant to Evista (CORE). Now 4 years into the trials, researchers have preliminarily reported a lack of cognitive decline.

Another agent being examined for risk reduction is a chlorinated derivative of tamoxifen, toremifene. This agent is approved for the treatment of breast cancer in postmenopausal women with ER-positive or receptor-unknown status tumors. Clinical experience with toremifene is limited. This agent has bone antiresorptive effects comparable to those of tamoxifen, but its effect on the uterus and endometrium has not been clearly defined in clinical trials. The risk of DVT is probably comparable to that for tamoxifen. Trials are under way in postmenopausal women comparing the efficacy of tamoxifen with toremifene for the adjuvant treatment of early-stage breast cancer.

Finally, some researchers see aromatase inhibitors as the wave of the future. Early but valid studies indicate that these agents, which block estrogen formation throughout the body, are approximately one third more effective at shrinking breast lesions than SERMs like tamoxifen. This evidence, plus the other data mentioned earlier in this article, indicate a role for endogenous estrogen in breast cancer development that is much more profound than that due to conventional doses of ERT/HRT.

Many unsettling questions remain to be answered. But evidence is still lacking that ERT or HRT contribute to breast cancer. Rather, there may be a marginal increase in diagnoses after a decade or more of ERT/HRT use that actually represents a very small number of cases per 1,000 women at risk. It remains to be seen whether the additional cases are a result of the increased longevity of women who receive ERT/HRT. On the other hand, there is considerable evidence that estrogen formed in the breast may play a key role in the development of breast cancer and that this local estrogen plays a dominant role in the disease’s cause.

Patients who are diagnosed with breast cancer and are on ERT/HRT have a better prognosis stage for stage, and large series appear to show no change in recurrence rates in women receiving ERT/HRT after apparently successful primary treatment for breast cancer. Mammography is the most successful tool in early diagnosis of breast cancer and the current controversy over mammography deals with the possibility that early diagnosis may lead to unnecessary treatment of early lesions whose propensity to metastasize is not yet defined. Tamoxifen, raloxifene, toremifene, and aromatase inhibitors are all very promising agents that obviate locally formed and circulating estrogens at the level of the breast. They have been shown effective in preventing and treating breast cancer.


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By Frederick Naftolin, MD, DPhil, Dahlia Mishell Sataloff, MD, and Trudy L. Bush, PhD, MHS

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