Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment.

Abstract

Glutathione S-transferase (GST) enzymes detoxify chemotherapeutic drugs, and several studies have reported differences in survival for cancer patients who have variant genotypes for GSTP1, GSTM1 or GSTT1 enzymes. A recently described polymorphism alters hepatic expression of GSTA1, a GST with high activity in glutathione conjugation of metabolites of cyclophosphamide (CP). To consider the possible influence of the reduced-expression GSTA1*B allele on cancer patient survival, we have conducted a pilot study of breast cancer patients treated with CP-containing combination chemotherapy. GSTA1 genotype was determined by polymerase chain reaction and restriction fragment length polymorphism. Kaplan-Meier methods and Cox proportional hazards models were used to evaluate survival in relation to genotype. Among 245 subjects, 35% were GSTA1*A/*A, 49% GSTA1*A/*B and 16% GSTA1*B/*B; the genotype distribution did not differ by ethnic group, age or stage at diagnosis. Among patients who had 0 or 1 GSTA1*B allele, the proportion surviving at 5 years was 0.66 (95% CI = 0.59-0.72), whereas for GSTA1*B/*B subjects the proportion was higher, 0.86 (95% CI = 0.67-0.95). Significantly reduced hazard of death was observed for GSTA1*B/*B subjects during the first 5 years after diagnosis, hazard ratio (HR) = 0.3, 95% CI = 0.1-0.8. The association varied with time, with no survival difference observed for subjects who survived beyond 5 years. These results, although based on a small study population, describe an apparent difference in survival after treatment for breast cancer according to GSTA1 genotype. Further studies should consider the possible association between the novel GSTA1*B variant and outcomes of cancer therapy.