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NESS 2006 Annual Meeting
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Of Mice and Men: the Role of Aberrant Crypt Foci as Surrogate Endpoint Biomarkers of Colorectal Cancer.
Nancy L. Cho1, Mark Redston1, Adelaide M. Carothers1, Ann G. Zauber2, Andrew Wilton2, Monica M. Bertagnolli1
1Brigham & Women's Hospital, Boston, MA;2Memorial Sloan-Kettering Cancer Center, New York, NY

Objective: Validate aberrant crypt foci (ACF) as surrogate endpoint biomarkers (SEB) of colorectal adenomas. Determine the role of estrogen (E2) and estrogen receptors (ER) in ACF/adenoma modulation in C57Bl/6J-Min/+ (Min/+) mice.
Design: Randomized placebo-controlled trial; patients examined at baseline and 8 months post-treatment.
Setting: University hospital.
Patients: Embedded cohort of 37 patients from the Adenoma Prevention with Celecoxib (APC) Trial matched for age, gender, adenoma burden, BMI, tobacco, and NSAID use.
Interventions: Patients treated with celecoxib 200 mg bid, celecoxib 400 mg bid, or placebo for 8 months.
Main Outcome Measures: Compare ACF number for patients on celecoxib and placebo detected by magnification chromoendoscopy relative to adenoma response. Compare ACF number in Min/+, ovariectomized Min/+ (OvxMin/+), and ER-deficient Min/+ mice relative to colon tumor numbers.
Results: H&E staining of 70 ACF from 37 patients showed all were hyperplastic. Despite celecoxib efficacy in preventing adenomas, the difference in ACF number was not significant for either celecoxib group relative to placebo. Immunohistochemistry for β-catenin identified 8 dysplastic ACF in 23 Min/+ colons but none in 23 OvxMin/+ colons. ER-deficient Min/+ strains demonstrated a significant increase in incidence of colon adenomas and a ~9-fold increase in ACF relative to ER+/+ Min/+ littermates.
Conclusions: Hyperplastic ACF are not reliable biomarkers of CRC, adenomas, or chemoprevention efficacy. ER signaling prevents adenoma and ACF formation in the Apc-deficient colon; E2 promotes dysplastic ACF, but not adenoma, formation in this tissue. Dysplastic ACF are not sufficient for adenoma formation in Min/+ mice.


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