The availability of clinical testing for germline mutations to BRCA1/2, and the high age-specific and lifetime breast cancer risks associated with these mutations contribute to heightened public awareness of the need for effective breast cancer prevention. At the same time, the Breast Cancer Prevention Trial (BCPT) has provided evidence that a reduction in breast cancer incidence can be effected through hormonal manipulation. Unfortunately, the mechanisms through which selective estrogen receptor modulators (SERMs( effect breast cancer prevention are not known. It is also unclear whether the preventive effect of these agents is sustained after cessation of therapy. The identification and evaluation of a biological markers in the proposed study is intended to elucidate each of these issues, and to provide markers for the evaluation of future hormonal chemopreventive agents. The proposed double blind, randomized, placebo-controlled trial will evaluate biomarkers of tamoxifen chemoprevention. Mammographic density will be the primary outcome. This marker has been correlated with breast cancer risk, and reduced breast density may have the added benefit of improving the sensitivity of breast cancer screening. We will employ breast density as a marker of progress-related (proliferative mechanisms of carcinogenesis. Secondary outcomes will include: 1) high risk estrogen profiles (derived project 4); and 2) markers of oxidative DNA damage, indicators of progression-related (pro-mutational) events in carcinogenesis. The responsiveness of each outcome will suggest the mechanism(s) through which tamoxifen exerts its preventive effect. The persistence of changes in the markers may provide early information about the duration of the tamoxifen effect; and the markers that respond to tamoxifen, a SERM that is known to be effective in breast cancer chemoprevention, may be employed in the evaluation of future hormonal preventive agents.
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