Analysis of the p53/BAX pathway in colorectal cancer: Low BAX is a negative prognostic factor in patients with resected liver metastases

Purpose: To determine the prognostic value of the central downstream apopto sis effector BAX in relation to its upstream regulator p53 in R0-resected h epatic metastases of colorectal cancer. Patients and Methods: Retrospective analysis of 41 patients who underwent p otentially curative resection of liver metastases from colorectal cancer wa s performed. Tumor DNA was screened for p53 mutations by single-stranded co nformational polymorphism polymerase chain reaction and for BAX frameshift mutations by fragment length analysis. protein expression of BAX, p21, and p53 was investigated by immunohistochemistry. Results: Overall median survival was 40.2 months. Tumors with BAX frameshif t mutations were considered microsatellite mutator phenotype-positive and w ere excluded from further prognostic analyses. Patients with high BAX prote in expression had a median survival of 53.6 months compared with 35.4 month s for patients with low BAX expression (P <.05). The negative prognostic va lue of low BAX expression was more evident in those patients with wild type p53 (median survival, 54.0 v 23.3 months for BAX-negative tumors; P <.01). Low BAX expression was an independent negative prognostic marker in multiv ariate regression analysis for all patients independent of the p53 status ( relative risk, 3.03, P =.03), especially for p53 wildtype tumors (relative risk, 8.21; P =.0095), Conclusion: We conclude that low BAX expression is an independent negative prognostic marker in patients with hepatic metastases of colorectal cancer, The best survival was seen in patients with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors. Thus, analysis of apoptosis sig naling pathways there, p53 in concert with its downstream death effector, B AX) might yield more prognostic power in future studies as compared with an alysis of single genes such as p53 alone. J Clin Oncol 17:1364-1374. (C) 19 99 by American Society of Clinical Oncology.