Breast cancer: pretreatment drug resistance parameters (GSH-system, ATase, P-glycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristics.
BACKGROUND
The identification of new factors predicting relapse, outcome and response to systemic therapy in breast cancer is warranted. The measurement of biological markers such as drug resistance parameters (DRPs), which are part of the phenotype of malignant cells and contribute to resistance to anti-cancer drugs may be a possibility, which may ultimately lead to improvement of therapeutic results.


METHODS
The level of glutathione (GSH), activities of glutathione-S-transferase (GST), glutathione-peroxidase (GPx), 06-alkylguanine-DNA-alkyltransferase (ATase), and P-glycoprotein (PGP) were measured in tumor and adjacent tumor free tissue samples from 89 consecutive, untreated females with breast cancer and correlated with clinical and prognostic factors. Early breast cancer (EBC) was diagnosed in 56 patients, 22 patients had locally advanced (LABC) and 11 patients metastatic breast cancer.


RESULTS
All DRPs showed significantly higher expression in tumor than in tumor free tissues. GPx was positively correlated with GST (r = 0.3, P = 0.0048) and with GSH (r = 0.5, P = 0.0001) in tumor as well as in normal tissue. GST activity was significantly higher in EBC than in LABC or metastatic breast cancer (P = 0.02). GSH level was significantly higher in grade 1 than in grade 2 or grade 3 tumors (P = 0.01). When clinical characteristics were related to the level of DRP, 'high' GSH was associated with age > 60 years (P = 0.01) in EBC, and with grade 1-2 tumors (P = 0.05) in LABC. No differences in OS were apparent between groups of 'high' and 'low' DRP-expression. However, the four-year estimated disease-free survival of EBC tended to be higher in patients with 'high' GST (P = 0.10) and of LABC in patients with 'high' GPx levels (P = 0.06).


CONCLUSIONS
We conclude that 'high' levels of DRP in tumor tissue of breast cancer patients are part of the initial phenotype of the malignant cells. Due to its high prevalence (83% in EBC, 100% in primarily metastatic breast cancer), PGP did not add to prognostic information. High levels of GSH, GST and GPx were associated with favorable clinical characteristics and good prognosis, whereas low levels of GSH and GST activity were associated with more aggressive or more advanced disease.
Buser
K
K
Institute for Medical Oncology, Inselspital, Bern, Switzerland.
Joncourt
F
F
Altermatt
H J
HJ
Bacchi
M
M
Oberli
A
A
Cerny
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019883:Alkyl and Aryl Transferases; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D014166:Transferases / Q000378:metabolism*; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005979:Glutathione Peroxidase; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C050956:DNA alkyltransferase; D005978:Glutathione