RISK BIOMARKERS AND CURRENT STRATEGIES FOR CANCER CHEMOPREVENTION

Quantifiable, well-characterized cancer risk factors demonstrate the n eed for chemoprevention and define cohorts for chemopreventive interve ntion. For chemoprevention, the important cancer risk factors are thos e that can be measured quantitatively in the subject at risk. These fa ctors, called risk biomarkers, can be used to identify cohorts for che moprevention. Those modulated by chemopreventive agents may also be us ed as endpoints in chemoprevention studies. Generally, the risk biomar kers fit into categories based on those previously defined by Hulka: 1 ) carcinogen exposure, 2) carcinogen exposure/effect, 3) genetic predi sposition, 4) intermediate biomarkers of cancer, and 5) previous cance rs. Besides their use in characterizing cohorts for chemoprevention tr ials, some risk biomarkers can be modulated by chemopreventive agents. These biomarkers may be suitable surrogate endpoints for cancer incid ence in chemoprevention intervention trials. The criteria for risk bio markers defining cohorts and serving as endpoints are the same, except that those defining cohorts are not necessarily modulated by chemopre ventive agents. A primary criterion is that the biomarkers fit expecte d biological mechanisms of early carcinogenesis-i.e., differential exp ression in normal and high-risk tissue, on or closely linked to the ca usal pathway for the cancer, and short latency compared with cancer. T hey must occur in sufficient number to allow their biological and stat istical evaluation. Further, the biomarkers should be assayed reliably and quantitatively, measured easily, and correlated to cancer inciden ce. Particularly important for cancer risk screening in normal subject s is the ability to use noninvasive techniques that are highly specifi c, sensitive, and quantitative. Since carcinogenesis is a multipath pr ocess, single biomarkers are difficult to correlate to cancer, as they may appear on only one or a few of the many possible causal pathways. As shown in colorectal carcinogenesis, the risks associated with the presence of biomarkers may be additive or synergistic. That is, the ac cumulation of genetic lesions is the more important determinant of col orectal cancer compared with the presence of any single lesion. Thus, batteries of biomarker abnormalities, particularly those representing the range of carcinogenesis pathways, may prove more useful than singl e biomarkers both in characterizing cohorts at risk and defining modul atable risks. Risk biomarkers are already being integrated into many c hemoprevention intervention trials. One example is the phase II trial of oltipraz inhibition of carcinogen-DNA adducts in a Chinese populati on exposed to aflatoxin B-1. Also, urine samples from subjects in this trial will be screened for the effect of oltipraz on urinary mutagens . A second example is a chemoprevention protocol developed for patient s at high risk for breast cancer; the cohort is defined both by heredi tary risk and the presence of biomarker abnormalities. Modulation of t he biomarker abnormalities is a proposed endpoint. Also, dysplastic le sions, such as prostatic intraepithelial neoplasia, oral leukoplakia a nd colorectal adenomas, have been used to define high-risk cohorts and as potential modulatable surrogate endpoints in chemoprevention trial s. (C) 1997 Wiley-Liss, Inc.(dagger)