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Prognostic Value of Thymidylate Synthase, Ki-67, and p53 in Patients With Dukes’ B and C Colon Cancer: A National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study

Carmen J. Allegra, Soon Paik, Linda H. Colangelo, Allyson L. Parr, Ilan Kirsch, George Kim, Pamela Klein, Patrick G. Johnston, Norman Wolmark, H. Samuel Wieand

From the Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; the National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; and the Department of Oncology, Belfast City Hospital, Northern Ireland.

Address reprint requests to Carmen J. Allegra, MD, 31 Center Dr, MSC 2440, Bldg 31, Rm 3A-44, Bethesda, MD 20892-2440; email: allegrac{at}navmed.nci.nih.gov.

Purpose: To define the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with stage II and III colon carcinoma.

Patients and Methods: We retrospectively analyzed the prognostic value of TS, Ki-67, and p53 in 706 patients with Dukes’ B (291 patients) or Dukes’ C (415 patients) colon carcinoma who were treated with either surgery alone (275 patients) or surgery plus fluorouracil (FU)-leucovorin chemotherapy (431 patients) in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols C01-C04. All three markers were assayed using immunohistochemical techniques.

Results: Using 5 years of follow-up data, our retrospective analysis demonstrated an association between TS intensity (relapse-free survival [RFS]: risk ratio [RR] = 1.46, P = .01; overall survival [OS]: RR = 1.54, P = .002), Ki-67 (RFS: RR = 0.76, P = .05; OS: RR = 0.62, P = .001), and p53 (RFS: RR = 1.49, P = .01; OS: RR = 1.21, P = .18) for RFS and OS. High TS intensity levels and positive p53 staining were associated with a worse outcome. Tumors containing a high percentage of Ki-67-positive cells enjoyed an improved outcome compared with those patients whose tumors contained relatively few positive cells. An interaction with treatment was not identified for any of the markers.

Conclusion: This retrospective investigation demonstrated that TS, Ki-67, and p53 staining each had significant prognostic value for patients with Dukes’ B and C colon carcinoma. However, none of the markers could be used to clearly discern groups of individuals who would be predicted to derive greater or lesser benefit from the use of adjuvant chemotherapy.

Supported by Public Health Service grants U10CA12027, U10CA69651, UC10CA37377, and U10CA69974 from the National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services, Bethesda, MD. This investigation was conducted after approval by a local and NCI Institutional Review Board committee and in accord with an assurance filed with and approved by the Department of Health and Human Services.

An abstract of this information was presented at the 2001 meeting of the American Society of Clinical Oncology as "Prognostic Value of Thymidylate Synthase, Ki-67, and p53 in Patients with Dukes’ B and C Colon Cancer."

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