Glutathione S-transferase P1 c.313A > G polymorphism could be useful in the prediction of doxorubicin response in breast cancer patients

Identification of predicting factors for anthracyclines-based chemotherapy remains a clinical challenge. Glutathione S-transferase (GSTs) enzymes detoxify chemotherapy drugs and their metabolites. Several polymorphisms in GST genes result in reduced or no activity of the enzymes. Specifically, GSTM1 and GSTT1 genes are polymorphically deleted, the polymorphism GSTP1 c.313A > G (rs1695) determines the amino acid substitution Ile(105)Val, where the Val-containing enzyme has reduced activity. Also, GSTA1*B allele has reduced levels of GSTA1 enzyme. Several polymorphisms in GSTs have been associated with differences in survival for cancer patients treated with chemotherapy. We genotyped a total of five polymorphisms in GSTM1, GSTT1, GSTP1 and GSTA1 genes in 159 patients with locally advanced breast cancer, treated with single-agent doxorubicin or docetaxel (Taxotere). Gene expression microarrays were performed in 67 breast tumor samples. We correlate this data with treatment outcome. In multivariate analysis, patients homozygous GG for GSTP1 c.313A > G SNP had a lower risk of chemoresistance when treated with doxorubicin (odds ratio 0.106; confidence interval 0.012-0.898; P = 0.040). No association was found in the docetaxel arm. Also, we found that GSTP1 expression varied significantly among breast cancer molecular subtypes. GSTP1 may constitute another tool contributing to individualized anthracycline-based therapy.