Zah. Khan et al., p53 mutation and response to hepatic arterial floxuridine in patients withcolorectal liver metastases, J CANC RES, 127(11), 2001, pp. 675-680
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.