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Investigation of the Prognostic and Predictive Value of Thymidylate Synthase, p53, and Ki-67 in Patients With Locally Advanced Colon Cancer

From the National Cancer Institute, Bethesda, MD; Mayo Clinic and Mayo Foundation, Rochester, MN; Meritcare Hospital Community Clinical Oncology Program, Fargo, ND; Illinois Oncology Research Association Community Clinical Oncology Program, Peoria, IL; Saskatoon Cancer Centre, Saskatoon; and Allan Blair Cancer Centre, Regina, Saskatchewan, Canada.

Address reprint requests to Richard M. Goldberg, MD, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; email: goldberg.richard@ mayo.edu.

PURPOSE: To evaluate the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with Dukes’ B2 and C colon carcinoma.

METHODS: We conducted a retrospective analysis to evaluate the prognostic value of TS, Ki-67, and p53 in 465 patients with Dukes’ B2 (220 patients) or Dukes’ C (245 patients) colon carcinoma. Patients represent a nonrandom subset obtained from five randomized phase III trials and were treated with either surgery alone (151 patients) or surgery plus fluorouracil-based chemotherapy (314 patients). All three markers were assayed using immunohistochemical techniques.

RESULTS: With a minimum follow-up of 5 years, our retrospective analysis failed to demonstrate a consistent and significant association between TS, Ki-67, or p53 and either disease-free survival or overall survival. Exploratory analyses did not reveal a convincing explanation for these results that are in conflict with the published literature. Notable interactions were observed. In particular, high Ki-67 levels were associated with increased (decreased) survival in patients with low (high) TS intensity. Patients whose tumors stained positively for p53 seemed to benefit substantially from the use of adjuvant chemotherapy compared with those who were not treated (P = .05).

CONCLUSION: This retrospective investigation failed to demonstrate a significant association between TS, Ki-67, or p53 staining and clinical outcome.

This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic.

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