TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients

We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.
Highlights • The TP53 status was found to be an independent predictive marker for the effect of adjuvant 5FU in stage III colon cancer. • In the N1 category, patients with wildtype TP53 experienced a significant survival benefit from adjuvant 5FU. • In TP53 mutant patients survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. Postoperative chemotherapy is recommended for all patients with lymph node positive colon cancer. In colon cancer, mutations in the TP53 gene are present in more than 30% of tumors. We found that the most commonly used postoperative chemotherapy resulted in a marked survival benefit for patients with normal TP53 status while it was associated with significant survival disadvantage in TP53 mutant patients. Overall the survival disadvantage of the mutated patients almost balanced the survival benefit of the TP53 normal patients. This might be an explanation why chemotherapy resulted in less progress in survival of colon cancer than we would have expected.