Giardiello, Frances

Abstract Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients enrolled in the Adenoma Prevention with Celecoxib (APC) Trial to determine whether the presence of ACF in the rectum correlated with that of adenomas in the entire large intestine. Participants were randomized to placebo (n=17), celecoxib 200 mg bid (n=15), or celecoxib 400 mg bid (n=13). Magnification chromoendoscopy (MCE) was performed to identify and biopsy ACF within the rectum at baseline and after 8-12 months of medication use. A total of 670 ACF were identified in 45 patients, and 70 of these were examined histologically. All of the ACF examined were non-dysplastic. Analysis showed no differences in ACF number between baseline and post-treatment studies (8.3±1.0 vs. 6.3±1.1) and no modulation by treatment (celecoxib vs placebo; p=0.77). Immunohistochemical studies showed that ACF contained cells exhibiting increased proliferation, but lacked other features of neoplasia such as increased Cox-2 expression and microvascular density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, estrogen receptor (ERα) or MGMT. Of the secondary markers assessed at baseline, only SMAD4 expression correlated with post-treatment adenoma recurrence. Taken together, these data showed that non-dysplastic ACF are not accurate surrogate endpoint biomarkers of colorectal adenoma risk or NSAID chemoprevention response.