p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients.
BACKGROUND
Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress.


METHODS
In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen.


RESULTS
Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12-0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088).


CONCLUSIONS
The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.
Wegman
Pia
P
Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, 581 85 Linköping, Sweden.
Stal
Olle
O
Askmalm
Marie Stenmark
MS
Nordenskjöld
Bo
B
Rutqvist
Lars-Erik
LE
Wingren
Sten
S
D000483:Alleles; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D003062:Codon; D005260:Female; D016158:Genes, p53; D014644:Genetic Variation; D006801:Humans; D011110:Polymorphism, Genetic; D018714:Radiotherapy, Adjuvant; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D003062:Codon; D013629:Tamoxifen