The Future Of Prevention

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

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Sporn and colleagues231,232 proposed the concept of the chemoprevention of cancer in the mid-1970s. Effective implementation of the strategy requires a target to prevent either the initiation or the promotion of the cancer cell.

The key to success is a well-defined target so that a selective action can be applied without general toxicity. In the case of breast cancer the target is the ERR,9 but serendipitously the antiestrogens tamoxifen and raloxifene, which block breast cancer cell growth, were also found to modulate the physiological requirements for estrogen action selectively at other target sites.15-17,233

The major clinical question for the current application of tamoxifen as a chemopreventive is when the 5-year course should be taken and how long the effects will protect a woman at elevated risk for breast cancer. The simple answer to the first part of the question is that a woman who fits the elevated risk criteria for breast cancer will receive benefit through a 55% risk reduction whenever she takes tamoxifen. However, since there are no rules that define when a woman will develop breast cancer, earlier rather than later would be an appropriate strategy. In regard to the duration of therapy, the answer is less clear; but there are clues that 5 years of tamoxifen therapy results in protection for at least 5 years after the drug is stopped, based on contralateral breast cancer data from the overview analysis.47 At this time, further follow-up is not available. It will be important to discover the mechanism for the long-term beneficial effects of tamoxifen as a chemopreventive as this could be exploited further. Similar questions about the optimal duration of raloxifene therapy will need to be addressed in the future. With raloxifene, this is not as important of an issue because long-term therapy for the prevention of osteoporosis is necessary.

The question of whether 5 years of tamoxifen will be sufficient for prolonged protection from breast cancer or whether longer durations of initial treatment will provide longer periods of protection remains unanswered. For example, after 10 or 15 years of treatment, can a woman get 20 years of risk reduction? There is reluctance to consider this type of clinical experiment because of concern over tamoxifen-stimulated primary breast cancer. Although 5 years of adjuvant tamoxifen appears to be as effective as 10 years,234 this does not justify restriction of chemopreven-tion to 5 years. Drug resistance by metastatic breast cancer cells can probably develop much more rapidly than during the process of car-cinogenesis in primary breast cancer. As a result, it may be important to evaluate longer durations of tamoxifen in clinical chemoprevention trials. The current challenge is to establish the efficacy of raloxifene compared with tamoxifen in the STAR trial and then to determine the optimal application of SERMs as a new drug group for the benefit of women's health.

Another unexplored aspect of chemoprevention with tamoxifen is evaluation of lower doses. This strategy may reduce side effects, while maintaining protection for the breast. Pilot studies have been completed in Italy,235,236 and clinical trials with large populations are planned. Finally, a new generation of agents that specifically modulate ERa and ERjS selectively may become available for clinical testing within the next decade.233 A number of postmenopausal diseases will be targeted, such as osteoporosis and coronary heart disease; but the beneficial side effects should include a reduction in uterine and breast cancers in the general population.237 The present reduction of breast cancer in high-risk women by 50% is an important first step that has resulted from the rational application of translational research.

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