title: Prognostic importance of thymidylate synthase expression in early breast cancer.
abstract: OBJECTIVE
  To assess the prognostic importance of thymidylate synthase (TS) expression in breast tumors of patients with early-stage breast cancer, and to determine whether the benefit of chemotherapy (CT) is associated with TS expression.
  
  
  METHODS
  The level of TS expression was evaluated in 210 node-negative and 278 node-positive patients enrolled onto Trial V of the International Breast Cancer Study Group ([IBCSG] formerly the Ludwig Breast Cancer Study Group) with a median follow-up time of 8.5 years. TS expression was assessed using the immunohistochemical method with the monoclonal antibody TS 106 on paraffin-embedded tissue specimens.
  
  
  RESULTS
  High TS expression was associated with a significantly worse prognosis in node-positive but not in node-negative breast cancer patients. Twenty-seven percent of node-positive patients with high TS expression were disease-free at 10 years, compared with 44% of node-positive patients with low TS expression (P = .03). Forty-one percent of patients with node-positive high-TS-expressing tumors were alive after 10 years, compared with 49% of those with low TS expression (P = .06). The association between TS and disease-free survival (DFS) and overall survival (OS) was independent of other prognostic factors such as tumor size, tumor grade, nodal status, vessel invasion, estrogen receptor (ER)/ progestin receptor (PR) status, c-erb B-2, or Ki-67 expression. In node-positive patients, six cycles of standard adjuvant cyclophosphamide, methotrexate, and fluorouracil ([5-FU] CMF) CT improved DFS and OS compared with one cycle of perioperative CMF therapy. The magnitude of this benefit was greatest in patients whose tumors had high TS expression (P < .01 for DFS; P < .01 for OS). Node-negative patients demonstrated no difference in outcome to CT based on TS expression; however, the power to detect differences was limited by the small number of events in this group.
  
  
  CONCLUSIONS
  In early-stage breast cancer, high TS expression is associated with a significantly worse prognosis in node-positive patients. Node-positive patients with high TS levels demonstrate the most significant improvement in DFS and OS when treated with six cycles of conventional adjuvant CMF therapy.
authors.affiliation: National Cancer Institute-Navy Medical Oncology Branch, Division of Clinical Sciences, Bethesda, MD, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Pestalozzi
authors.forename: H F
authors.initials: HF
authors.lastname: Peterson
authors.forename: R D
authors.initials: RD
authors.lastname: Gelber
authors.forename: A
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: B A
authors.initials: BA
authors.lastname: Gusterson
authors.forename: H
authors.initials: H
authors.lastname: Trihia
authors.forename: J
authors.initials: J
authors.lastname: Lindtner
authors.forename: H
authors.initials: H
authors.lastname: Cortés-Funes
authors.forename: E
authors.initials: E
authors.lastname: Simmoncini
authors.forename: M J
authors.initials: MJ
authors.lastname: Byrne
authors.forename: R
authors.initials: R
authors.lastname: Golouh
authors.forename: C M
authors.initials: CM
authors.lastname: Rudenstam
authors.forename: M
authors.initials: M
authors.lastname: Castiglione-Gertsch
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
authors.forename: P G
authors.initials: PG
authors.lastname: Johnston
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D013940:Thymidylate Synthase; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate