title: Prognostic of DNA-synthesizing enzyme activities (thymidine kinase and thymidylate synthase) in 908 T1-T2, N0-N1, M0 breast cancers: a retrospective multicenter study.
abstract: Among the methodological approaches of tumor proliferation, thymidine kinase (TK) and thymidylate synthase (TS) assays take into account the specific pathways of pyrimidine synthesis. Studies pointing to a prognostic value of TK and TS in breast cancer involved small numbers of patients. We investigated the prognostic value of these enzymes and their combination in a large retrospective multicenter study. Nine hundred eight T1T2, N0N1, M0 primary breast cancer samples (median follow-up 68 months) were tested. TK and TS were measured in cytosols by using standardized radioenzymatic methods. Although a positive correlation was obtained between TK and TS (p<10(-5)), major discrepancies were observed in some tumors. High levels of both enzymes were associated with large tumor size, histological grade III and steroid receptor-negative tumors. Univariate analysis showed that TK, TS and their combination were predictive of poor metastasis-free (MFS) (p < 10(-4); p=0.004; p < 10(-4)) and disease-free survival (DFS) (p < 10(-4); p=0.007; p=0.0001). TK was selected as an independent factor for MFS in Cox analysis. It was the only variable selected in node-negative patients. Subgroups with specific outcomes, with possible therapeutic implications, were identified: a) in node-negative patients not receiving adjuvant treatment, TK values in the 4th quartile were associated with poor MFS (p=0.0002) and DFS (p=0.0005) as compared to the other quartiles; b) in node-positive patients receiving adjuvant chemotherapy, low levels of both TK and TS were associated with the highest survival rates (MFS: p=0.04; DFS: p=0. 03).
authors.affiliation: AP-HM, Marseille, France. sromain@ap-hm.fr
authors.forename: S
authors.initials: S
authors.lastname: Romain
authors.forename: F
authors.initials: F
authors.lastname: Spyratos
authors.forename: F
authors.initials: F
authors.lastname: Descotes
authors.forename: A
authors.initials: A
authors.lastname: Daver
authors.forename: B
authors.initials: B
authors.lastname: Rostaing-Puissant
authors.forename: P
authors.initials: P
authors.lastname: Bougnoux
authors.forename: M
authors.initials: M
authors.lastname: Colonna
authors.forename: M
authors.initials: M
authors.lastname: Bolla
authors.forename: P M
authors.initials: PM
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D003600:Cytosol / Q000201:enzymology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013937:Thymidine Kinase / Q000032:analysis*; D013940:Thymidylate Synthase / Q000032:analysis*
chemical_list: D009363:Neoplasm Proteins; D013940:Thymidylate Synthase; D013937:Thymidine Kinase