Neoplasia is a progression of molecular, cellular, and tissue changes starting with a critical cell mutation and advancing by clonal evolution, involving further multiple mutations and expanding mutated clones. This process is characterized by five general stages: latency, focal growth of normal-appearing but disorganized cells, abnormal-appearing cells (dysplasia), microinvasion, and finally, metastasis. The two driving forces of neoplastic progression in an epithelium are mutagenesis and mitogenesis. These forces frequently occur concurrently, produced by exposure of the epithelium to environmental and endogenous mutagens and mitogens. The major strategy of chemoprevention is to block the effects of both mutagens and mitogens during the early stages of predysplasia and dysplasia.
Surrogate endpoint biomarkers (SEBs) are tissue, cellular, and molecular changes that correlate with the later development of cancer. Because of the savings in cost, labor, and time, SEBs are urgently needed to replace the use of cancer incidence reduction as the endpoint for chemopreventive agent clinical trials. The advent of computer-assisted cytometry allows each of the seven basic criteria of dysplasia to be individually assayed as an SEB. Since the dysplastic changes that characterize intraepithelial neoplasia are embodied in the causal pathway to invasive neoplasia, they are already validated as predictors of cancer incidence. More attention should be paid to the quality control of SEB assays, including control of variation in cell composition of tissue samples, assay protocol, instrumentation used, and observer performance. The dose-response relationship between a known chemopreventive agent and the SEB should also be evaluated.
The Division of Cancer Prevention and Control, National Cancer Institute, has begun a program to test chemopreventive agents in short-term Phase I1 clinical trials using dysplasiabased SEBs. The SEBs are assayed, when possible, by computerized cytometry. Trials are being conducted for oral leukoplakia, cutaneous actinic keratosis, superficial bladder cancer, pulmonary metaplasia/dysplasia, cervical dysplasia (CIN 111), and adenomatous colonic polyps.