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Prognostic Value of Proliferation, Apoptosis, Defective DNA Mismatch Repair, and p53 Overexpression in Patients With Resected Dukes' B2 or C Colon Cancer

A North Central Cancer Treatment Group Study

From the Mayo Clinic and Mayo Foundation, Rochester; CentraCare Clinic, St Cloud; The Duluth Clinic, Duluth, MN; Cedar Rapids Oncology Project CCOP, Cedar Rapids; Siouxland Hematology-Oncology Associates, Sioux City, IA; University of North Carolina Department of Hematology/Oncology, Chapel Hill, NC; Allegheny General Hospital, Pittsburgh, PA; and Allan Blair Cancer Centre, Regina, Saskatchewan, Canada

Address reprint requests to Thomas E. Witzig, MD, 6-28 Stabile Building, 200 First St SW, Rochester, MN 55905; e-mail: witzig{at}mayo.edu

PURPOSE: Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas.

PATIENTS AND METHODS: Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS).

RESULTS: Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P < .05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P < .01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant.

CONCLUSION: This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.

Supported by the National Cancer Institute Grant (CA78899) and conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.

Presented as an abstract for oral presentation at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Work for this study was completed at the Mayo Clinic, Rochester, MN.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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