Development of surrogate endpoint biomarkers for clinical trials of cancer chemopreventive agents: relationships to fundamental properties of preinvasive (intraepithelial) neoplasia.
The tissue changes offering the greatest immediate potential for development as surrogate endpoint biomarkers (SEBs) to be used in Phase II trials of cancer chemopreventive agents are those derived from the microscopic tissue changes pathologists use to make the diagnosis of preinvasive (intraepithelial) neoplasia. These changes comprise four categories: proliferative index, ploidy, nuclear morphometry (size, shape, texture, and pleomorphism), and nucleolar morphometry (number, size, shape, position, and pleomorphism). Computer-assisted image analysis (CIA) permits dozens of additional morphometric parameters to be developed. Other categories of candidate SEBs are: DNA and chromosomal structural changes associated with genomic instability, activation of oncogenes and inactivation of tumor suppressor genes, structural changes in differentiated molecules, and aberrations of growth factor/receptor structure and function. Self-perpetuating DNA breakage with secondary mutator mutations in genomic stability genes is a major mechanism by which the genomic instability characteristic of neoplasia occurs, and from which stem other basic neoplastic properties, including clonal evolution, along multiple pathways of genetic variation that are stochastically determined, continuously increasing proliferation, rate and extent of phenotypic heterogeneity. SEBs resulting from genomic instability include homogeneously staining regions, double minute chromosomes, micronuclei, dicentrics, gene amplification, loss of heterozygosity, and alterations in chromosome number. Newly developed assays for detecting genomic instability include comparative genomic hybridization using fluorescence in situ hybridization on > 20 micron-thick sections monitored by confocal laser scanning microscopy, assays for microsatellite instability, and restriction landmark genomic scanning. These assays offer promise for detecting the earliest molecular changes of neoplasia in normal-appearing epithelium prior to the onset of the dysplastic phase of intraepithelial neoplasia.
Boone
C W
CW
Chemoprevention Investigational Studies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Kelloff
G J
GJ
D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002986:Clinical Trials as Topic; D004848:Epithelium / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000473:pathology* / Q000517:prevention & control / Q000648:ultrastructure; D013269:Stochastic Processes
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor