Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803

Abstract

Purpose: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer.

Experimental design: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL).

Results: TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men.

Conclusions: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men.

Figure 1

(A) Structure of the p53 DNA binding domain. The zinc binding regions are cyan for L2, magenta for L3, and orange for LSH; non-zinc binding regions are gray; the zinc atom (Zn) is yellow. Image was rendered using PyMOL 1.4.1 software and p53 crystal structure PDB ID: 1TSR. (B) Missense mutations in the DNA binding domain. Codons encompassing zinc binding (ZB) mutations are denoted by colored horizontal bars spanning L2 (codons 163–195), L3 (codons 236–251) and LSH (codons 273–286); non-zinc binding (NZB) mutations are denoted by gray bars. Codon numbers are provided for hotspots.

Figure 2

Kaplan-Meier estimate of disease-free survival related to (A) TP53 genotype (WT = wild type; Mutant = any TP53 mutation in exons 5–8) among all patients evaluated, P = 0.86. (B-D), Kaplan-Meier estimates of disease-free survival related to TP53 status (WT = wild type; ZB = zinc binding mutation; NZB = non-zinc binding mutation) among: (B) all patients evaluated, P = 0.20; (C) women, P = 0.008; and (D) men, P = 0.36. Corresponding 5 year survival estimates are in Table 1, Rows 11–13.

Figure 3

Kaplan-Meier estimate of disease-free survival related to TP53 genotype (WT = wild type; ZB = zinc binding mutation; NZB = non-zinc binding mutation) among (A) women treated with 5FU/LV, P = 0.0006; and (B) women treated with IFL, P = 0.82. Corresponding 5 year survival estimates are in Table 2, Rows 14–15.