p53 mutation and response to hepatic arterial floxuridine in patients withcolorectal liver metastases

Purpose: To establish the relationship between the number and site of p53 g enomic mutations in metastatic colorectal cancer, and the response to hepat ic arterial floxuridine Methods: Liver metastasis biopsies were collected, at the time of laparotomy for hepatic arterial cannulation, in 28 patients with metachronous colorectal liver metastases. p53 Gene mutations were asse ssed using reverse transcription, nested polymerase chain reaction, single strand conformational polymorphism and gene sequencing. Chemotherapy respon se was determined from computerised liver tomograms after 4 months of treat ment. Results: Liver metastasis p53 mutation was identified in 21 (75%), an d p53 "hot spot" mutation in 11 (39%) patients. There was a significantly l ower prevalence (Fisher's, P = 0.001) of patients with p53 "hot spot"-mutat ed liver metastases in stable disease and partial response (5/22) than in p rogressive (6/6) disease groups. Significantly fewer (Mann-Whitney U, P = 0 .002) p53 "hot spot" mutations//biopsy were observed in liver metastases fr om stable disease and partial response (median 0. iqr. 0-0) than in progres sive (median 1, iqr 1-2) disease patients. p53 "Hot spot"-mutated liver met astases were associated with significantly shorter survival times (logrank P = 0.05) after hepatic arterial floxuridine. Significant response or survi val-time differences by total or L2/L3 zinc-binding site p53 mutations were not detected. Conclusions: The results support a role for p53 "hot spot" m utations in colorectal liver metastasis resistance to fluorinated pyrimidin es, and suggest that the presence of such mutations may be a contra-indicat ion to treatment of colorectal liver metastases with hepatic arterial floxu ridine.