STRATEGIES FOR THE APPLICATION OF BIOMARKERS FOR RISK ASSESSMENT AND EFFICACY IN BREAST-CANCER CHEMOPREVENTION TRIALS

Current chemoprevention trial designs based on epidemiological risk as sessment and occurrence of cancer as an endpoint are inefficient and e xpensive. Novel biomarkers are needed to facilitate the development of chemopreventive interventions. The following four categories of bioma rkers may be useful in prevention trials: histologic and morphometric markers; phenotypic markers of dysregulated proliferation, differentia tion, and cell loss; specific oncogenes and growth regulators which ar e qualitatively or quantitatively altered in breast cancers; and marke rs of genetic and epigenetic instability. Some of these markers will b e generally useful regardless of the chemopreventive approach used, wh ereas others may be uniquely useful in trials of specific chemoprevent ive agents [e.g., upregulation of progesterone receptor (PR) expressio n in response to tamoxifen]. The development of these markers requires three phases of study: ''Phase I'': assessing the prevalence of the p utative marker in malignant and premalignant tissue from individuals. who have developed breast cancer; ''Phase II'': assessing in vivo modu lation of the biomarker by the proposed chemopreventive agent; and ''P hase III'': applying the proposed biomarker in larger-scale trials of chemopreventive agent in high-risk populations, either before or after the development of a primary breast malignancy. The use of these biom arkers may also allow identification of novel targets for chemoprevent ion. (C) 1993 Wiley-Liss, Inc.