Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer

Background: Members of the glutathione S-transferase (GST) superfamily are important in cellular defense mechanisms. These enzymes attach reduced glutathione to electrophilic groups in a wide variety of toxic compounds, including chemotherapeutic agents. Certain polymorphisms in GSTs are associated with changes in enzyme activity, sensitivity to chemotherapy, and overall patient survival. In a retrospective study, we investigated associations between common polymorphisms in genes for several GST subclasses (GSTP1, GSTT1, GSTM1) and survival of patients with metastatic colorectal cancer receiving 5-fluorouracil (5-FU)/oxaliplatin chemotherapy. Methods: During 1998-2000, 107 previously treated patients with advanced colorectal cancer received 5-FU/oxaliplatin combination chemotherapy. Associations between deletion polymorphisms in GSTM1 and GSTT1 genes and between a polymorphism in the GSTP1 gene that generates an Ile¹⁰⁵Val in the GSTP1 protein and survival were evaluated using relative risks (RRs) of dying and the log-rank test. All statistical tests were two-sided. Results: Patients heterozygous for the GSTP1 polymorphism had an RR = 0.47 (95% confidence interval [CI] = 0.27 to 0.81) compared with patients homozygous for the GSTP1 ¹⁰⁵Ile allele. Patients homozygous for the mutant polymorphism had an RR = 0.16 (95% CI = 0.04 to 0.63). After adjustment for performance status and tumor site, the stratified RRs were 0.28 (95% CI = 0.07 to 1.10) for patients with two ¹⁰⁵Val alleles and 0.64 (95% CI = 0.36 to 1.16) for those with one ¹⁰⁵Val allele (P = 0.42). Patients with the ¹⁰⁵Val/¹⁰⁵Val genotype survived a median of 24.9 months, those with the ¹⁰⁵Ile/¹⁰⁵Ile genotype a median of 7.9 months, and those with the ¹⁰⁵Ile/¹⁰⁵Val genotype a median of 13.3 months (P<.001). The GSTM1 and GSTT1 genotypes were not associated with survival or clinical response. Conclusions: The GSTP1 Ile¹⁰⁵Val polymorphism is associated in a dose-dependent fashion with increased survival of patients with advanced colorectal cancer receiving 5-FU/oxaliplatin chemotherapy.