Journal of Clinical Oncology, Vol 20, Issue 7
(April), 2002: 1721-1728
© 2002 American Society for Clinical Oncology
Thymidylate Synthase Expression in Colorectal Cancer: A Prognostic and Predictive Marker of Benefit From Adjuvant Fluorouracil-Based Chemotherapy
By David Edler,
Bengt Glimelius,
Marja Hallström,
Anders Jakobsen,
Patrick G. Johnston,
Inger Magnusson,
Peter Ragnhammar,
Henric Blomgren
From the Department of Surgery, South Hospital, Stockholm; Department of Oncology, Uppsala Akademiska Hospital, Uppsala; Department of Oncology Karolinska Hospital, Stockholm, Sweden; Department of Oncology, Vejle Hospital, Vejle, Denmark; and Department of Oncology, Queens University of Belfast, Belfast, Northern Ireland.
Address reprint requests to David Edler, MD, Department of Surgery, Karolinska Hospital, S-17176 Stockholm, Sweden; email: david.edler{at}swipnet.se
PURPOSE: We studied the prognostic value of thymidylate synthase (TS) expression in primary colorectal cancer (CRC) and the role of TS expression as a predictor of chemotherapeutic benefit in patients treated with adjuvant chemotherapy.
PATIENTS AND METHODS: TS expression was immunohistochemically assessed on tumor sections from 862 patients with CRC Dukes’ stages B and C enrolled onto randomized trials evaluating fluorouracil (5-FU)-based adjuvant chemotherapy.
RESULTS: TS expression was an independent prognostic factor for disease-free (P = .05) and overall survival (P = .05). In the subgroup treated with surgery alone, TS was an independent prognostic factor for disease-free (P < .001) and overall survival (P = .001), whereas this was not the case in the subgroup of adjuvantly treated patients. Patients whose tumors expressed high TS levels had a tendency to improved outcome after adjuvant therapy (not significant). The group whose tumors expressed the highest TS grade, grade 3 (34% of the patients), had a significantly longer disease-free survival if they were treated with adjuvant therapy compared with surgery alone (multivariate analyses, P = .02), whereas patients whose tumors expressed low TS levels (28% of the patients) had an impaired outcome after adjuvant therapy (multivariate analyses: disease-free survival, P = .01; overall survival, P = .01).
CONCLUSION: TS expression predicts for survival independent of Dukes’ stage in patients with CRC treated with surgery alone. The study indicates that patients with high TS levels may benefit from adjuvant 5-FU–based chemotherapy. However, patients with low TS levels seem to have a worse outcome when treated with adjuvant chemotherapy.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
G. Lurje, P. C. Manegold, Y. Ning, A. Pohl, W. Zhang, and H.-J. Lenz
Thymidylate synthase gene variations: predictive and prognostic markers
Mol. Cancer Ther.,
May 1, 2009;
8(5):
1000 - 1007.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Sturgeon, M. J. Duffy, U.-H. Stenman, H. Lilja, N. Brunner, D. W. Chan, R. Babaian, R. C. Bast Jr., B. Dowell, F. J. Esteva, et al.
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers
Clin. Chem.,
December 1, 2008;
54(12):
e11 - e79.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Wilson, W. Fazzone, M. J. LaBonte, J. Deng, N. Neamati, and R. D. Ladner
Novel opportunities for thymidylate metabolism as a therapeutic target
Mol. Cancer Ther.,
September 1, 2008;
7(9):
3029 - 3037.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Soong, N. Shah, M. Salto-Tellez, B. C. Tai, R. A. Soo, H. C. Han, S. S. Ng, W. L. Tan, N. Zeps, D. Joseph, et al.
Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy
Ann. Onc.,
May 1, 2008;
19(5):
915 - 919.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Kim, L. H. Colangelo, H. S. Wieand, S. Paik, I. R. Kirsch, N. Wolmark, and C. J. Allegra
Prognostic and Predictive Roles of High-Degree Microsatellite Instability in Colon Cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study
J. Clin. Oncol.,
March 1, 2007;
25(7):
767 - 772.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Seve, R. Lai, K. Ding, T. Winton, C. Butts, J. Mackey, C. Dumontet, L. Dabbagh, S. Aviel-Ronen, L. Seymour, et al.
Class III {beta}-Tubulin Expression and Benefit from Adjuvant Cisplatin/Vinorelbine Chemotherapy in Operable Non-Small Cell Lung Cancer: Analysis of NCIC JBR.10
Clin. Cancer Res.,
February 1, 2007;
13(3):
994 - 999.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Han and S. Galandiuk
Induction Chemoradiation for Rectal Cancer
Arch Surg,
December 1, 2006;
141(12):
1246 - 1252.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S Popat, Z Chen, D Zhao, H Pan, N Hearle, I Chandler, Y Shao, W Aherne, and R. Houlston
A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer
Ann. Onc.,
December 1, 2006;
17(12):
1810 - 1817.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Sinicrope, R. L. Rego, K. C. Halling, N. R. Foster, D. J. Sargent, B. La Plant, A. J. French, C. J. Allegra, J. A. Laurie, R. M. Goldberg, et al.
Thymidylate synthase expression in colon carcinomas with microsatellite instability.
Clin. Cancer Res.,
May 1, 2006;
12(9):
2738 - 2744.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Dotor, M. Cuatrecases, M. Martinez-Iniesta, M. Navarro, F. Vilardell, E. Guino, L. Pareja, A. Figueras, D. G. Mollevi, T. Serrano, et al.
Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment
J. Clin. Oncol.,
April 1, 2006;
24(10):
1603 - 1611.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Garcia, J. M. Garcia, C. Pena, J. Silva, G. Dominguez, A. Hurtado, I. Alonso, R. Rodriguez, M. Provencio, and F. Bonilla
Thymidylate synthase messenger RNA expression in plasma from patients with colon cancer: prognostic potential.
Clin. Cancer Res.,
April 1, 2006;
12(7):
2095 - 2100.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. L. Gomez, S. L. Santillana, C. S. Vallejos, R. Velarde, J. Sanchez, X. Wang, N. L. Bauer, R. D. Hockett, V. J. Chen, C. Niyikiza, et al.
A Phase II Trial of Pemetrexed in Advanced Breast Cancer: Clinical Response and Association with Molecular Target Expression
Clin. Cancer Res.,
February 1, 2006;
12(3):
832 - 838.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Westra, H. Hollema, M. Schaapveld, I. Platteel, K. A. Oien, W. N. Keith, R. Mauritz, G. J. Peters, C. H. C. M. Buys, R. M. W. Hofstra, et al.
Predictive value of thymidylate synthase and dihydropyrimidine dehydrogenase protein expression on survival in adjuvantly treated stage III colon cancer patients
Ann. Onc.,
October 1, 2005;
16(10):
1646 - 1653.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Ohrling, D. Edler, M. Hallstrom, P. Ragnhammar, and H. Blomgren
Detection of Thymidylate Synthase Expression in Lymph Node Metastases of Colorectal Cancer Can Improve the Prognostic Information
J. Clin. Oncol.,
August 20, 2005;
23(24):
5628 - 5634.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Ahlgren
Thymidylate Synthase in Nodal Metastases: Prognostic for Chemosensitivity But Not for Adjuvant Therapy?
J. Clin. Oncol.,
August 20, 2005;
23(24):
5452 - 5454.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Perathoner, D. Pirkebner, G. Brandacher, G. Spizzo, S. Stadlmann, P. Obrist, R. Margreiter, and A. Amberger
14-3-3{sigma} Expression Is an Independent Prognostic Parameter for Poor Survival in Colorectal Carcinoma Patients
Clin. Cancer Res.,
May 1, 2005;
11(9):
3274 - 3279.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Kidd, J. Yu, X. Li, W. D. Shannon, M. A. Watson, and H. L. McLeod
Variance in the Expression of 5-Fluorouracil Pathway Genes in Colorectal Cancer
Clin. Cancer Res.,
April 1, 2005;
11(7):
2612 - 2619.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Popat, A. Matakidou, and R. S. Houlston
In Reply:
J. Clin. Oncol.,
March 20, 2005;
23(9):
2108 - 2109.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Jakobsen, J. N. Nielsen, N. Gyldenkerne, and J. Lindeberg
Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphism in Normal Tissue As Predictors of Fluorouracil Sensitivity
J. Clin. Oncol.,
March 1, 2005;
23(7):
1365 - 1369.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kamoshida, H. Matsuoka, T. Ishikawa, K. Maeda, R. Shimomura, K.-i. Inada, and Y. Tsutsumi
Immunohistochemical Evaluation of Thymidylate Synthase (TS) and p16INK4a in Advanced Colorectal Cancer: Implication of TS Expression in 5-FU-based Adjuvant Chemotherapy
Jpn. J. Clin. Oncol.,
October 1, 2004;
34(10):
594 - 601.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Koehler and R. D. Ladner
Small Interfering RNA-Mediated Suppression of dUTPase Sensitizes Cancer Cell Lines to Thymidylate Synthase Inhibition
Mol. Pharmacol.,
September 1, 2004;
66(3):
620 - 626.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T.-L. Wang, L. A. Diaz Jr., K. Romans, A. Bardelli, S. Saha, G. Galizia, M. Choti, R. Donehower, G. Parmigiani, I.-M. Shih, et al.
Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients
PNAS,
March 2, 2004;
101(9):
3089 - 3094.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Popat, A. Matakidou, and R. S. Houlston
Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Systematic Review and Meta-Analysis
J. Clin. Oncol.,
February 1, 2004;
22(3):
529 - 536.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-J. Sohn, R. Croxford, Z. Yates, M. Lucock, and Y.-I. Kim
Effect of the Methylenetetrahydrofolate Reductase C677T Polymorphism on Chemosensitivity of Colon and Breast Cancer Cells to 5-Fluorouracil and Methotrexate
J Natl Cancer Inst,
January 21, 2004;
96(2):
134 - 144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Odin, Y. Wettergren, S. Nilsson, R. Willen, G. Carlsson, C. P. Spears, L. Larsson, and B. Gustavsson
Altered Gene Expression of Folate Enzymes in Adjacent Mucosa Is Associated with Outcome of Colorectal Cancer Patients
Clin. Cancer Res.,
December 1, 2003;
9(16):
6012 - 6019.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kornmann, W. Schwabe, S. Sander, M. Kron, J. Strater, S. Polat, E. Kettner, H. F. Weiser, W. Baumann, H. Schramm, et al.
Thymidylate Synthase and Dihydropyrimidine Dehydrogenase mRNA Expression Levels: Predictors for Survival in Colorectal Cancer Patients Receiving Adjuvant 5-Fluorouracil
Clin. Cancer Res.,
September 15, 2003;
9(11):
4116 - 4124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. C. Hu, R. A. Komorowski, S. Graewin, G. Hostetter, O.-P. Kallioniemi, H. A. Pitt, and S. A. Ahrendt
Thymidylate Synthase Expression Predicts the Response to 5-Fluorouracil-based Adjuvant Therapy in Pancreatic Cancer
Clin. Cancer Res.,
September 15, 2003;
9(11):
4165 - 4171.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Tsuji, S. Hidaka, T. Sawai, T. Nakagoe, H. Yano, M. Haseba, H. Komatsu, H. Shindou, H. Fukuoka, M. Yoshinaga, et al.
Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Is Not an Efficacious Marker for Tumor Sensitivity to 5-Fluorouracil-based Oral Adjuvant Chemotherapy in Colorectal Cancer
Clin. Cancer Res.,
September 1, 2003;
9(10):
3700 - 3704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Graziano and S. Cascinu
Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough?
Ann. Onc.,
July 1, 2003;
14(7):
1026 - 1038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Bertino and D. Banerjee
Is the Measurement of Thymidylate Synthase to Determine Suitability for Treatment with 5-Fluoropyrimidines Ready for Prime Time?
Clin. Cancer Res.,
April 1, 2003;
9(4):
1235 - 1239.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Allegra and D. Sargent
Molecular Diagnostics: Assays, Tissues, Progress, and Pitfalls
J. Clin. Oncol.,
February 1, 2003;
21(3):
395 - 396.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gonen, A. Hummer, A. Zervoudakis, D. Sullivan, Y. Fong, D. Banerjee, D. Klimstra, C. Cordon-Cardo, J. Bertino, and N. Kemeny
Thymidylate Synthase Expression in Hepatic Tumors Is a Predictor of Survival and Progression in Patients With Resectable Metastatic Colorectal Cancer
J. Clin. Oncol.,
February 1, 2003;
21(3):
406 - 412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Allegra, S. Paik, L. H. Colangelo, A. L. Parr, I. Kirsch, G. Kim, P. Klein, P. G. Johnston, N. Wolmark, and H. S. Wieand
Prognostic Value of Thymidylate Synthase, Ki-67, and p53 in Patients With Dukes' B and C Colon Cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study
J. Clin. Oncol.,
January 15, 2003;
21(2):
241 - 250.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N J Maughan and P Quirke
Pathology - a molecular prognostic approach: Advances in colorectal cancer
Br. Med. Bull.,
December 1, 2002;
64(1):
59 - 74.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Derenzini, L. Montanaro, A. Chilla, E. Tosti, C. Ceccarelli, F. Dall'Olio, D. Ofner, and D. Trere
Evaluation of Thymidylate Synthase Protein Expression by Western Blotting and Immunohistochemistry on Human Colon Carcinoma Xenografts in Nude Mice
J. Histochem. Cytochem.,
December 1, 2002;
50(12):
1633 - 1640.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Allegra
Thymidylate Synthase Levels: Prognostic, Predictive, or Both?
J. Clin. Oncol.,
April 1, 2002;
20(7):
1711 - 1713.
[Full Text]
[PDF]
|
|
|
|
