Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S-transferase genetic polymorphisms as predictive biomarkers of disease outcome.
BACKGROUND
The glutathione S-transferases (GSTs) are a group of multifunctional enzymes that catalyze the conjugation of glutathione with a variety of electrophilic compounds, including cytotoxic agents. A significant percentage of normal individuals exhibit genetic polymorphism with a homozygous deletion (null genotype) of the genes, leading to absence of the enzyme.


METHODS
In the present study we analyzed GSTM1 and GSTT1 polymorphisms in the genomic DNA isolated from peripheral blood of patients with ovarian cancer treated with chemotherapy (paclitaxel and cisplatinum) after cytoreductive surgery and assessed its correlation with the clinical outcome of these patients. The median follow-up for the patients was 30 months.


RESULTS
The estimated 3-year survival rate was 59.8% for all patients and 20.8% for carriers of GSTM1-wt/GSTT1-wt (wt indicates wild type) genotype combination (37.7% for GSTM1-wt alone) compared with 83.1% for non-GSTM1-wt/GSTT1-wt genotype carriers (100% for GSTM1-null). The mean survival time was significantly better in patients who are carriers of the GSTM1-null genotype (40.5 vs. 33.5; P=0.006) or carriers of non-GSTM1-wt/ GSTT1-wt genotypes (55.4 vs. 30.7; P=0.009). The progression-free interval was more favorable for GSTM1-null carriers (41.9 vs. 27.4; P=0.024).


CONCLUSIONS
The study suggests that characterization of the drug-metabolizing genetic individual profile can be of great interest in clinical oncology. It can define the optimal chemotherapy for each patient, improve the efficiency, and reduce the incidence of drug toxicity and poor drug responses.
Medeiros
Rui
R
Unit of Molecular Oncology, Laboratórios-PISO 4, Instituto Português de Oncologia-Porto, R. Dr. Ant. Bernardino Almeida, 4200-072 Porto, Portugal. ruimmms@mail.com
Pereira
Deolinda
D
Afonso
Noémia
N
Palmeira
Carlos
C
Faleiro
Cristina
C
Afonso-Lopes
Carlos
C
Freitas-Silva
Margarida
M
Vasconcelos
André
A
Costa
Sandra
S
Osório
Teresa
T
Lopes
Carlos
C
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D002945:Cisplatin / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011336:Probability; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D005982:Glutathione Transferase; D017239:Paclitaxel; D002945:Cisplatin