Prognostic importance of thymidylate synthase expression in early breast cancer.
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.
Pestalozzi
B C
BC
National Cancer Institute-Navy Medical Oncology Branch, Division of Clinical Sciences, Bethesda, MD, USA.
Peterson
H F
HF
Gelber
R D
RD
Goldhirsch
A
A
Gusterson
B A
BA
Trihia
H
H
Lindtner
J
J
Cortés-Funes
H
H
Simmoncini
E
E
Byrne
M J
MJ
Golouh
R
R
Rudenstam
C M
CM
Castiglione-Gertsch
M
M
Allegra
C J
CJ
Johnston
P G
PG
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*
D009363:Neoplasm Proteins; D013940:Thymidylate Synthase; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate