Glutathione S-transferase M1 null genotype: lack of association with tumour characteristics and survival in advanced breast cancer.
BACKGROUND
Glutathione S-transferase (GST)M1, a member of the mu class GST gene family, has been shown to be polymorphic because of a partial gene deletion. This results in a failure to express the GSTM1 gene in 50-60% of individuals. Several studies have demonstrated a possible link with the GSTM1-null genotype and susceptibility to cancer. Furthermore, a GSTM1 isoenzyme has been positively associated with protective effect against mutagenic drugs, such as alkylating agents and anthracyclines.


OBJECTIVE
To determine whether GSTM1 polymorphisms are associated with tumour characteristics and survival in advanced breast cancer patients, and whether it may constitute a prognostic factor.


METHODS
We genotyped 92 patients receiving primary chemotherapy, which included cyclophosphamide, doxorubicine and 5-fluorouracil. The relationships between allelism at GSTM1 and clinicopathological parameters including age, menopausal status, tumour size, grade hormone receptors, involved nodes and p53 gene mutations were analysed. Of the patients with GSTM1-positive genotype, tissue samples obtained before and after treatment were available from 28 cases, allowing RNA extraction and GSTM1 expression by reverse transcription polymerase chain reaction. Relationships with clinical response to chemotherapy, and disease-free and overall survival were also evaluated. The data obtained was analysed using logistic regression to estimate the odds ratio and 95% confidence interval.


RESULTS
Of 92 patients, 57.6% (n = 53) were classified as heritably GSTM1-deficient, and 42.4% (n = 39) were of the GSTM1-positive genotype. There were no statistically significant relationships between GSTM1-null genotype and the clinicopathological parameters analysed. No relationship was observed between GSTM1 RNA expression and objective clinical response to chemotherapy. Objective clinical response to chemotherapy was related only to clinical tumour size (P = 0.0177) and to the absence of intraductal carcinoma (P = 0.0013). GSTM1-null genotype had no effect on disease-free or overall survival. The absence of hormone receptors (P = 0.002), the presence of a mutated p53 gene (P = 0.0098) and lack of response to primary chemotherapy (P = 0.0086) were the only factors associated with reduced disease-free or overall survival.


CONCLUSIONS
GSTM1-null genotype alone had no effect on tumour characteristics and outcome of patients with advanced breast cancers. The lack of correlation of GSTM1 genotype with clinical tumour features, clinical response to chemotherapy and survival exclude a role for GSTM1 polymorphism as a prognostic factor in advanced breast cancer.
Lizard-Nacol
S
S
Laboratory of Molecular Genetics, Centre Georges-François Leclerc, 1 rue du Professeur Marion, 21034 Dijon Cedex, France. Slizard@dijon.fnclcc.fr
Coudert
B
B
Colosetti
P
P
Riedinger
J M
JM
Fargeot
P
P
Brunet-Lecomte
P
P
D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged
D005982:Glutathione Transferase