Polymorphisms in manganese superoxide dismutase, myeloperoxidase and glutathione-S-transferase and survival after treatment for metastatic breast cancer

Abstract

Treatments for metastatic breast cancer (MBC) are primarily palliative with variable efficacy and outcomes may be influenced by individual differences in drug metabolism. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in genes involved in drug metabolism with progression free survival (PFS) and breast cancer specific survival (BCSS) in 95 patients with MBC that received high dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT). SNPs in the SOD2 (SOD2-01, Val16Ala), MPO (MPO-02, -463 promoter variant) and GSTP1 [GSTP1-01 (Ile105Val), GSTP1-02 (Ala114Val)] genes were examined in DNA isolated from cryopreserved blood products using genotyping assays. Survival was analysed using Cox proportional hazard models and Kaplan-Meier estimates. Patients with the SOD2-01 (TT) genotype had increased risk of disease progression [hazard ratio (HR): 2.52; 95% confidence interval (CI), 1.31-4.85] and breast cancer specific death (HR: 1.92; 95% CI: 1.03-3.57). Risks were increased for patients with both SOD2-01 (TT) and GSTP1-01 (GG or AG) genotypes (HR for disease progression: 2.57, 95% CI: 1.32-5.00 and HR for breast cancer specific death: 2.27; 95% CI: 1.18-4.34). In multivariable analysis, the combined genotype group of SOD2-01 and GSTP1-01 was an independent predictor of PFS and BCSS. HRs progressively increased with increasing number of genotypes associated with worse survival, with p(trend) of 0.005 and 0.006 for PFS and BCSS, respectively. These results suggest that SNPs in genes involved in drug metabolism may influence survival outcome for patients with MBC receiving HDC and ASCT.

Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case–control study of contralateral breast cancer risk in the WECARE Study

“…Comparison between studies is complicated by the inclusion of different SNPs in different genes. Prior studies have shown that some variants in CYPs and GSTs can alter the pharmacokinetics of CTX metabolism [27, 29, 30] and influence clinical response and toxicity of CTX-based chemotherapies [31–38]. Other studies have found no association between genetic variants in these genes and CTX pharmacokinetics [39] or outcome [40].…”

Nucleotide excision repair polymorphisms and survival outcome for patients with metastatic breast cancer

“…These are listed in Table 1 and have been previously described (Bewick et al 2006(Bewick et al , 2008. The clinical trials and study were approved by the Research Ethics Board, Sudbury Regional Hospital, Sudbury, Ontario, and informed signed consent was obtained from all patients.…”

“…Single nucleotide polymorphisms (SNPs) in genes in these pathways may significantly affect DNA repair efficiency (Au et al 2004;Abdel-Rahman and El-Zein 2000;Duell et al 2000), drug toxicity and clinical outcomes following treatment with cancer drugs and/or radiation (Booton et al 2006;Ambrosone et al 2006;Gurubhagavatula et al 2004;Kamikozuru et al 2008). The influence of individual gene polymorphisms on treatment outcome may be moderate, but reports from our laboratory (Bewick et al 2006(Bewick et al , 2008 and others Ambrosone et al 2005;Nagle et al 2007;Nowell et al 2005) suggest that combinations of polymorphisms in several genes may significantly impact clinical responses and survival.…”

There is no relationship between SOD2 Val-16Ala polymorphism and breast cancer risk or survival

“…By reading the full texts, 11 studies were out of scope as they did not satisfy the inclusion criteria (one meeting abstract, three animal experiments or cell cultures and seven without available data). Finally, a total of 34 publications were available for the present meta-analysis, 26 for risk analysis and eight for survival analysis (58)(59)(60)(61)(62)(63)(64)(65). The flow chart of study search and inclusion was demonstrated in Fig.…”