Surrogate endpoint biomarker assays in phase II chemoprevention clinical trials

Surrogate endpoint biomarker (SEB) assays carried out in rodent models have benefitted from large amounts of available colonic tissue, abundant well-aligned colonic crypts, and population groups with fairly uniform biological characteristics. In contrast, SEB assays in human colon studies have often been carried out on small groups of subjects, without the advantages inherent in rodent studies. Some factors that contribute to variations in human colon SEB assays include differences in genetic background, the extent and duration of previous colonic diseases, degree of previous chronic irritation to the colonic mucosa, the initial levels of nutrients ingested prior to the study, administration of large volumes of fluid prior to SEB measurement which induce hypermetabolic and then quiescent changes in the mucosa, failure to use strict morphologic criteria in counting colonic crypts, and availability of only a small number of crypts for analysis. Measurements of adenoma recurrence over short durations are limited by factors that include a large potential miss-rate of small adenomas, a window of observation with short duration which limits the stage of adenoma observed, and the consequent inability to measure mechanisms that a chemopreventive intervention is affecting in a different stage of adenoma development.