Aberrant crypt foci in the adenoma prevention with celecoxib trial.
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 beta-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor alpha, 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.
Cho
Nancy L
NL
Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
Redston
Mark
M
Zauber
Ann G
AG
Carothers
Adelaide M
AM
Hornick
Jason
J
Wilton
Andrew
A
Sontag
Stephen
S
Nishioka
Norman
N
Giardiello
Francis M
FM
Saltzman
John R
JR
Gostout
Chris
C
Eagle
Craig J
CJ
Hawk
Ernest T
ET
Bertagnolli
Monica M
MM
D000236:Adenoma / Q000175:diagnosis / Q000473:pathology / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D007414:Intestinal Neoplasms / Q000175:diagnosis / Q000473:pathology / Q000517:prevention & control*; D007417:Intestinal Polyps / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011230:Precancerous Conditions / Q000473:pathology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D010919:Placebos; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib