Summary of recommendations for colonic biomarker studies of candidate chemopreventive compounds in phase II clinical trials

Abstract

New genetic, morphologic, proliferative and differentiation-associated biomarkers are available for study in Phase II chemoprevention clinical trials. These biomarkers have potential as surrogate intermediate endpoints for cancer incidence and eventual tumor inhibition. At this meeting, approaches to improve the standardization and quality control of biomarker assays were considered. Useful biomarkers should be amenable to quality control monitoring; sensitive, specific, and precise; sensitive to modulation by chemopreventive agents; and simple enough to be performed routinely in research or clinical laboratories. Human studies have more factors that contribute to biomarker assay variation than rodent studies. These include: (1) wider differences in genetic background of study subjects; (2) differing extent and duration of previous colonic diseases; (3) varying amounts of chronic irritation in the colonic mucosa of "normal" subjects induced by exposure to dietary and other factors; (4) differing initial levels of study nutrients ingested prior to the study; (5) administration of fluids prior to biomarker measurement which are followed by biopsies after hypermetabolic changes become quiescent; (6) failure to use strict morphologic criteria in counting fewer available human colonic crypts; (7) amplifying field variations in colonic mucosa by decreasing the number of colonic crypts counted; (8) colonoscopic miss-rate of adenomas; (9) a clinical trial window of observation of short duration which limits the stage of adenoma development that is measured; and (10) failure to measure the activity of a chemopreventive agent during the stage of adenoma development in which it is active. Some of these points are relevant to chemopreventive agents used in clinical trials involving other organs.(ABSTRACT TRUNCATED AT 250 WORDS)