GLUTATHIONE-S-TRANSFERASE ACTIVITY IN EPITHELIAL OVARIAN-CANCER - ASSOCIATION WITH RESPONSE TO CHEMOTHERAPY AND DISEASE OUTCOME

Background. Conflicting data have been reported about the association between glutathione S-transferase (GST), a family of proteins implicat ed in detoxification of cytotoxic drugs in human ovarian in vitro mode ls, and response to chemotherapy and prognosis in ovarian cancer patie nts. The aim of this study was to analyze the possible clinical role o f GST activity in a large series of primary ovarian cancer patients. P atients and methods. The study included a large series of primary untr eated ovarian cancer patients who underwent cytoreductive surgery and chemotherapy and who were followed up in a single institution. GST act ivity levels were assessed in tumor extracts by using a biochemical as say. A cutoff of 250 units of enzymatic activity was chosen according to the receiver operating characteristics (ROC) curve. Results. GST ac tivity levels were distributed in an asymmetrical manner (median: 266 units; range: 4-918 units) and did not seem to be associated with stag e, histopathological grading, ascites, or residual tumor after surgery Higher GST activity levels were found in patients who responded to ch emotherapy (median: 298 units, range: 50-691) than in those who respon ded only partially (median: 227 units, range: 19-747) or not at all to chemotherapy (median: 246 units, range: 4-811) (H = 7.02, P = 0.029). Moreover, the percentage of cases with > 250 units was significantly higher among complete responders (66%) than partial responders (37%) o r non-responders (48%) (chi(2) = 7.32; P = 0.025). When multivariate a nalysis, including clinico-pathological parameters and GST activity st atus as predictors of response to chemotherapy, was carried out, resid ual tumor, stage and GST status retained independent predictive value. Patients with high GST activity had more favourable prognosis than th ose with low GST activity. The median PFS was 42 months for patients w ith high GST activity compared to 17 months for those with low GST act ivity (P = 0.037). The median overall survival was 72 months for high- GST-activity and 42 months for low-GST-activity patients (P = 0.043). Substantially similar results were obtained in the subgroup of stage I I-III-IV ovarian cancer patients. Multivariate analysis including the clinico-pathological parameters and GST activity status was performed in stage III-IV ovarian cancer patients: Stage IV disease, residual tu mor > 2 cm, the presence of ascites and low GST activity status retain ed independent negative prognostic roles. Conclusion. A direct associa tion between high GST activity and a better clinical outcome in terms of response to chemotherapy and survival has been observed in a large series of primary untreated ovarian cancer patients. These results, wh ich are contrary to the expectations raised by in vitro studies: empha size the need for caution when translating in vitro-generated hypothes es to the clinical setting.