Analysis of neuroendocrine differentiation and the p53/BAX pathway in UICC stage III colorectal carcinoma identifies patients with good prognosis.

BACKGROUND AND AIMS: Neuroendocrine differentiation is an independent prognostic factor in colorectal cancer. Moreover, an altered p53/BAX pathway is associated with a poor clinical outcome in Union Internationale Contre le Cancer (UICC) stage III disease. Because these markers are involved in different genetic events disrupted in colorectal cancer, we investigated the prognostic power of a multimarker analysis. PATIENTS AND METHODS: Specimens were analyzed from 59 patients with UICC stage III disease who underwent surgery for colorectal adenocarcinoma at our institution and were followed up for 5 years or until death. Tumors were studied for both p53 mutation and BAX protein expression as well as for the expression of neuroendocrine markers. Statistical analysis of each marker alone or in combination was performed. RESULTS: p53 status/BAX expression and neuroendocrine differentiation are not correlated in stage III colorectal cancers. However, the combination of both independent events identified a subgroup of patients with an excellent prognosis: Patients whose tumors were neuroendocrine marker-negative and who exhibited an intact p53/BAX pathway lived longer (mean survival, 93 months; range, 82-104 months) than patients whose tumors were either neuroendocrine marker-positive or whose tumors had a completely disrupted apoptotic pathway (41 months; range, 26-57 months; p<0.00001). In multivariate regression analysis, neuroendocrine marker-positive, p53 mutated, low-BAX-expressing tumors revealed an almost fivefold higher risk for earlier death (p<0.0001). CONCLUSION: Disruption of the p53/BAX pathway is not pathognomonic for colorectal cancers with neuroendocrine differentiation. Both represent independent prognostic markers in UICC stage III disease. Therefore, the combined analysis of p53 status, BAX expression and neuroendocrine differentiation allows one to identify subgroups of patients with either very good or very poor prognosis.

Analysis of p53/BAX in primary colorectal carcinoma: low BAX protein expression is a negative prognostic factor in UICC stage III tumors.

Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p < 0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p = 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/BAX pathway (i.e., BAX low/p53 mutated; p = 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.