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. © 2002 Wiley-Liss, Inc. Key words: glutathione S-transferase; polymorphism; breast cancer; survivalInherited polymorphisms in enzymes that activate or detoxify chemotherapy drugs are thought to account for some of the variability in toxicity and efficacy of cancer treatment. 1 The GST enzymes catalyze the glutathione-dependent detoxification of several chemotherapeutic drugs or their metabolites. 2,3 Polymorphisms that result in reduced (e.g., GSTP1 single nucleotide polymorphisms [SNP]) or no (e.g., GSTM1 and GSTT1 deletion polymorphisms) activity of certain GST enzymes are recognized. These polymorphisms may alter the metabolism of chemotherapeutic drugs and modify the effectiveness of therapy, as suggested by reports that GST polymorphisms predict differences in outcomes of treatment for cancers including breast cancer, 4 -6 leukemias 7-10 and colorectal cancer. 11 GSTA1 and other GSTs of the ␣ class are the predominant GSTs in human liver, 12,13 the major site of drug metabolism, and are also expressed in other tissues. 14,15 In vitro studies have shown that among human GSTs, GSTA1 has the highest catalytic activity for glutathione conjugation of nitrogen mustard chemotherapy agents, 3 including metabolites of cyclophosphamide (CP), 16 which is used in combination chemotherapy for breast cancer. A poly...

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21

“…The association of GSTA1 rs3957357 and CYBA rs4673 with R-CHOP21 efficacy and DLBCL outcome is biologically plausible and consistent with previous observations in settings other than lymphoma. 10,15,[29][30][31][32][33] GSTA1 encodes an alpha1 class glutathione S-transferase that catalyses the conjugation of cyclophosphamide and its active metabolites with glutathione to increase water solubility and facilitate excretion. 15 The GSTA1 rs3957357T minor allele associates with reduced levels of GSTA1 enzyme in healthy individuals, and predicts for Pharmacogenetics of R-CHOP21 in DLBCL D Rossi et al reduced detoxification of alkylating agents, thus increasing tumor cell exposure to drug.…”

“…In fact, the GSTA1 rs3957357T minor allele has been shown to associate with improved survival of breast cancer patients treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or cyclophosphamide, adriamycin and 5-fluorouracil (CAF). 31 Although a formal pharmacokinetic proof is lacking, it is conceivable that improved outcome in both DLBCL and breast cancer may be related to increased levels of cyclophosphamide derivatives mediating increased tumor cell killing. Beside its impact on efficacy, GSTA1 rs3957357 also impacts on the risk of infective toxicity in DLBCL (this study) as well as in other clinical settings treated with cyclophosphamide containing regimens.…”

Genetic polymorphisms in glutathione‐S‐transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma

“…The results of such studies have been mixed. [12][13][14][15][16] Ambrosone et al 13 and Sweeney et al 14 found that clinical outcomes after chemotherapy were significantly associated with certain GST polymorphisms, whereas no effect was reported in other studies. 12,16 Studies of different populations, and particularly larger cohorts, clearly are needed.…”

“…[12][13][14][15][16] Ambrosone et al 13 and Sweeney et al 14 found that clinical outcomes after chemotherapy were significantly associated with certain GST polymorphisms, whereas no effect was reported in other studies. 12,16 Studies of different populations, and particularly larger cohorts, clearly are needed. In the current study, we evaluated overall survival in association with polymorphisms in the GSTM1, GSTT1, and GSTP1 genes in 1034 Chinese patients who were treated with chemotherapy for primary invasive breast carcinoma between 1996 and 1998 and who were followed for a median of 5.3 years.…”

GSTA1 (glutathione S-transferase alpha 1)

“…In breast cancer patients on cyclophosphamide containing chemotherapy carriers of GSTA1*B/*B genotype showed significantly reduced five years risk of death in comparison to GSTA1*A homozygous carriers. This association was likely caused by decreased detoxification of the therapeutic metabolites of cyclophosphamide in GSTA1*B/*B patients (Sweeney et al, 2003).…”