Strategies for Chemoprevention
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-01 trial compared tamoxifen with placebo in women whose breast cancer risk over a 5-year period was at least 1.6% as calculated by the Gail Model. Although a 50% reduction in breast cancer incidence was seen, the trial has been unblinded and many control subjects are now taking tamoxifen, so no mortality data will be available.
The results of the P-01 trial contrast those of 2 similar trials in the United Kingdom and Italy, which failed to demonstrate any benefit for prophylactic tamoxifen. This was particularly striking in the United Kingdom trial, where there was a preponderance of women who were at high risk based on a strong family history, and who may have been carriers of mutations in BRCA1 or BRCA2.
The higher prevalence of hormone receptor-negative breast cancers in mutation carriers may account, at least in part, for the lack of benefit of tamoxifen in this trial. At a minimum, the discordant results of these 3 trials suggest there may be subgroups of women who do not benefit from prophylactic tamoxifen.In a similar fashion, raloxifene has been reported to reduce breast cancer risk in women who participated in studies that examined the effect of the drug on osteoporosis risk.
The effect on breast cancer risk was a secondary outcome of these studies, and firm conclusions regarding its benefit will require additional evidence from the ongoing follow-up of women enrolled in existing trials[15,16] as well as from new trials in new groups of women. The ongoing NSABP P-02 or Study of Tamoxifen and Raloxifene (STAR) trial, which is comparing tamoxifen with raloxifene in high-risk women, will likely provide important information in this area.
Placebo-controlled trials in the area of breast cancer chemoprevention can help to address specific questions. For example, in P-01, nearly 80 women took tamoxifen for 5 years for each breast cancer that was prevented (usually a low-risk breast cancer). Is prevention better than cure? Would it have been better to simply treat the breast cancers? Also, which women do not benefit from prophylactic tamoxifen? Do those with mutations in BRCA1 or BRCA2 not benefit? Are there other groups that do not benefit? Further trials are clearly needed to elucidate these and other issues in chemoprevention.
"Finally, in lower-risk women, such as those with a single first-degree relative with breast cancer, a randomized trial of phytoestrogen supplementation might be considered."
Kathleen I. Pritchard, MD and Pamela Goodwin, MD, MSc, FRCP
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