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

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 wild-type 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 wild-type GSTT1/GSTM1. The six gene combinations associated with the largest number of responding patients were found to contain the wild-type GSTP1105Ile and the polymorphic-type GSTM1"null". These specific combinations were virtually absent in the combinations with few responding patients.

Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer.

Primary chemotherapy is a useful strategy for the treatment of locally advanced breast cancer and therefore allows in vivo evaluation of the action of cytotoxic drugs and the possibility of accomplishing conservative breast surgeries, as well as the early treatment of metastasis. Mechanisms of resistance to the drugs include the action of protein associated with the efflux of drugs from the intracellular environment hindering their activity; one of the most studied proteins is P-glycoprotein codified by the MDR-1 gene. The presence of polymorphisms can determine different physiological actions of these proteins, intervening with the response of the drug's action. We evaluated the presence of single nucleotide polymorphism (SNP) C3435T of the MDR-1 gene and its correlation with the response to primary chemotherapy using the RECIST criteria. Forty-one Brazilian women with stages II and III breast cancer using the PCR-RFLP analysis were evaluated. Thirty-three patients with the SNP genotype (TT and CT) and eight patients with the wild genotype (CC) were found; there was no statistically significant correlation between the diverse genotypes and the clinical and pathological responses according to the Cramer correlation coefficient (V = 0.14). The parameters: nuclear and histological degree, and estrogens, progesterone and c-erb B2 receptors did not demonstrate a statistical correlation with the SNP C3435T. Patients with complete pathological response (12.5%) showed only the polymorphic genotype and not the wild genotype. The characteristics of miscegenation in our population could explain the absence of the characterization of a sub-group of individuals where the presence of the polymorphic genotype influenced the response to the primary chemotherapy.

Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer

Primary chemotherapy is a useful strategy for the treatment of locally advanced breast cancer and therefore allows in vivo evaluation of the action of cytotoxic drugs and the possibility of accomplishing conservative breast surgeries, as well as the early treatment of metastasis. Mechanisms of resistance to the drugs include the action of protein associated with the efflux of drugs from the intracellular environment hindering their activity; one of the most studied proteins is P-glycoprotein codified by the MDR-1 gene. The presence of polymorphisms can determine different physiological actions of these proteins, intervening with the response of the drug’s action. We evaluated the presence of single nucleotide polymorphism (SNP) C3435T of the MDR-1 gene and its correlation with the response to primary chemotherapy using the RECIST criteria. Forty-one Brazilian women with stages II and III breast cancer using the PCR-RFLP analysis were evaluated. Thirty-three patients with the SNP genotype (TT and CT) and eight patients with the wild genotype (CC) were found; there was no statistically significant correlation between the diverse genotypes and the clinical and pathological responses according to the Cramer correlation coefficient (V = 0.14). The parameters: nuclear and histological degree, and estrogens, progesterone and c-erb B2 receptors did not demonstrate a statistical correlation with the SNP C3435T. Patients with complete pathological response (12.5%) showed only the polymorphic genotype and not the wild genotype. The characteristics of miscegenation in our population could explain the absence of the characterization of a sub-group of individuals where the presence of the polymorphic genotype influenced the response to the primary chemotherapy.