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Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial

Authors' Affiliations: Departments of ¹ Surgery, ² Pathology, and ³ Medicine, Brigham and Women's Hospital; ⁴ Department of Medicine, Massachusetts General Hospital, Boston Massachusetts; ⁵ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center; ⁶ Pfizer, Inc., New York, New York; ⁷ Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; ⁸ Hines Veteran's Administration Medical Center, Hines, Illinois; ⁹ Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland; ¹⁰ Department of Medicine, The Mayo Clinic, Rochester, Minnesota; and ¹¹ National Cancer Institute, Bethesda, Maryland

Correspondence: Requests for reprints: Monica M. Bertagnolli, Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-8910; Fax: 617-582-6177; E-mail: mbertagnolli{at}partners.org.

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 randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor , or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.

Commentary

Sporadic Aberrant Crypt Foci Are Not a Surrogate Endpoint for Colorectal Adenoma Prevention

Peter Lance and Stanley R. Hamilton
Cancer Prevention Research 2008 0: 194062070. [Abstract]