GSTT1, GSTM1, and GSTP1 polymorphisms and chemotherapy response in locally advanced breast cancer

Abstract

ABSTRACT. The glutathione S-transferase (GST) family consists of phase II detoxification enzymes that catalyze the conjugation of toxic substances, such as chemotherapeutic agents, to glutathione. We examined whether GSTT1/GSTT1"null", GSTM1/GSTM1"null" and GSTP1Ile105Ile/GSTP1Ile105Val polymorphisms are associated with different response rates to neoadjuvant chemotherapy in the treatment of stage II and III breast cancer. Forty Brazilian women with invasive ductal adenocarcinoma of the breast submitted to neoadjuvant chemotherapy, using 5-fluorouracil, epirubicin and cyclophosphamide, were genotyped for the GSTT1, GSTM1 and GSTP1 genes. Clinical response was assessed by RECIST criteria. Comparisons were made for the three genes alone and in pairs, as polymorphic and as wildtype combinations and polymorphic/wild-type combinations. We analyzed all possible combinations and their response rate. Patients with the GSTT1/GSTP1105Ile combination were found to have a significantly better response than GSTT1"null"/GSTP1105Val (P = 0.0209) and GSTT1/GSTM1 (P = 0.0376) combinations. Analysis of all possible combinations showed the GSTM1"null" polymorphic genotype to be present in four, and the wild-type GSTP1105Ile in six of the combinations associated with the largest number of responding patients. We found that patients with the GSTT1/GSTP1105Ile wild-type combination had a significantly higher response rate to chemotherapy than patients with the respective polymorphic GSTT1"null"/GSTP1105Val combination or patients with the wildtype GSTT1/GSTM1. The six gene combinations associated with the largest number of responding patients were found to contain the wildtype GSTP1105Ile and the polymorphic-type GSTM1"null". These specific combinations were virtually absent in the combinations with few responding patients.

Prospective Case–Control Study to Evaluate the Role of Glutathione S Transferases (GSTT1 and GSTM1) Gene Deletion in Breast Carcinoma and Its Prognostic Significance

“…The GST has been shown to have activity both by direct detoxification of the drugs themselves or through detoxification of lipid hydro peroxides generated by the cytotoxic drugs [12]. In addition, the GSTs are also involved in cell signaling pathways that control stress response, apoptosis, and cellular proliferation [13]. Thereby, the polymorphisms in the genes of these enzymes could contribute to tumor cell survival and drug resistance by causing detoxification of products of cancer chemotherapy.…”

Genetic polymorphisms of glutathione S transferase and cervical intraepithelial neoplasia

“…As only a part of the HPV infected women develop precancerous cervical lesions or cancer, prophylactic evaluation of GST family enzymes could play a major role in identifying high risk individuals for an efficient therapeutic interference, here including HPV vaccination (42,43).…”

Predictive Role of GSTs on the Prognosis of Breast Cancer Patients with Neoadjuvant Chemotherapy

“…However, there are few studies in Chinese breast cancer patients. Only several studies conducted in western countries investigation the association of GSTs with chemotherapy response and survival of breast cancer, but the results are conflicting (Satta et al, 1992;Whelan et al, 1992;Ott et al, 2008;Lourenço et al, 2010;Oliveira et al, 2010;Mishra et al, 2011). A study conducted in Brasil showed combination of null GSTT1 and GSTP1 105Val have poor response than combination of non-null GSTT1 and GSTP1 105IIe (Oliveira et al, 2010).…”

“…Only several studies conducted in western countries investigation the association of GSTs with chemotherapy response and survival of breast cancer, but the results are conflicting (Satta et al, 1992;Whelan et al, 1992;Ott et al, 2008;Lourenço et al, 2010;Oliveira et al, 2010;Mishra et al, 2011). A study conducted in Brasil showed combination of null GSTT1 and GSTP1 105Val have poor response than combination of non-null GSTT1 and GSTP1 105IIe (Oliveira et al, 2010). However, another study in Indian, it did not find a significant association between glutatinione S-transferases and responses to chemotherapy (Mishra et al, 2011), and another study conducted in Germany did not found a significant responses to chemotherapy among individuals with GSTT1, GSTM1 and GSTP1 (Ott et al, 2008).…”