title: 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.
authors.affiliation: Division of Epidemiology, University of Minnesota, Minneapolis, MN 55454, USA. sweeney@epi.umn.edu
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Lija
authors.initials: L
authors.lastname: Joseph
authors.forename: Angie
authors.initials: A
authors.lastname: Stone
authors.forename: Laura F
authors.initials: LF
authors.lastname: Hutchins
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Brian F
authors.initials: BF
authors.lastname: Coles
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D016022:Case-Control Studies; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D007527:Isoenzymes; D003520:Cyclophosphamide; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha