Thymidylate synthase and p53 expression do not predict chemotherapy outcome in metastatic colorectal carcinoma

Berglund, Å.; Edler, David; Nordlinder, Hans; Molin, Daniël; Graf, Wilhelm; Glimelius, Bengt

doi:10.1016/s0959-8049(01)81562-8

Cited by 5 publications

(4 citation statements)

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“…However, as previously pointed out21 this observation was likely to reflect a bias of RTPCR‐based methods in dichotomising TS, since the thresholds were defined as those most likely to predict disease response. Other studies found no association of TS32, 33, 34, 35 or DPD36, 37 levels with outcome of advanced colorectal cancer.…”

Section: Discussionmentioning

confidence: 90%

The prognostic significance of thymidylate synthase and dihydropyrimidine dehydrogenase in colorectal cancer of 303 patients adjuvantly treated with 5‐fluorouracil

Jensen

Vainer

Sørensen

2006

Intl Journal of Cancer

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Cytotoxic effect of 5-fluorouracil 5-FU is mediated through inhibition of thymidylate synthase (TS), and 5-FU is catabolised by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5-FU may therefore depend on the TS and DPD activity of colorectal cancer. Archival tumour specimens from 303 consecutive patients were analysed for the expression of TS and DPD using immunohistochemistry. All patients were completely resected for colorectal cancer stages II-III and have subsequently received adjuvant treatment with 5-FU. In a multivariate analysis adjusting for the impact of bowel obstruction and vascular tumour invasion, diffuse TS pattern was significantly associated with increased risk of recurrence (hazard ratio (HR) 5 1.9; 95% confidence interval (CI): 1.1-3.2; p 5 0.02), but without significant association to death (HR 5 1.6; 95% CI: 0.9-2.8; p 5 0.08). High TS intensity was not significantly associated with lower risk of recurrence (HR 5 0.6; 95% CI: 0.3-1.1; p 5 0.07) or death (HR 5 0.6; 95% CI: 0.3-1.2; p 5 0.2). High DPD intensity was significantly associated with increased risk of recurrence (HR 5 1.5; 95% CI: 1.1-2.3; p 5 0.03) and death (HR 5 1.6; 95% CI: 1.1-2.5; p 5 0.02). Patients with a combination of low TS and high DPD intensity were at significantly increased risk of both recurrence (HR 5 2.1; 95% CI: 1.0-4.2; p 5 0.04) and death (HR 5 2.0; 95% CI: 1.0-4.0; p 5 0.05). No relationship between tolerability and toxicity of 5-FU and TS and DPD expression was found. It is concluded that characterizing colorectal carcinomas by TS and DPD expression may disclose subsets of patients with significantly greater risk of disease recurrence and early death. This may be utilized in the selection of patients for treatment approaches and for decision on follow-up programs. ' 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 90%

The prognostic significance of thymidylate synthase and dihydropyrimidine dehydrogenase in colorectal cancer of 303 patients adjuvantly treated with 5‐fluorouracil

Jensen

Vainer

Sørensen

2006

Intl Journal of Cancer

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“…Unfortunately, the studies that were trying to predict response to palliative 5-FU treatment in metastatic colorectal cancer using TS measurement of the primary tumour failed to demonstrate a clear association [38][39][40]. This observation is, however, not surprising when one considers the fact that several studies have shown that there is no correlation between levels of TS in primary tumours compared with metastatic lesions, the former tending to have higher levels [41,42].…”

Section: Ts As a Prognostic And Predictive Factor In Advanced Diseasementioning

confidence: 99%

Thymidylate synthase expression and prognosis of patients with gastrointestinal cancers receiving adjuvant chemotherapy: a review

Formentini

Henne‐Bruns

Kornmann

2004

Langenbecks Arch Surg

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Patients with gastrointestinal cancers that express high TS levels have a poor prognosis with regard to fluoropyrimidine-based palliative chemotherapy or complete primary tumour resection. In contrast, patients with high TS levels might benefit from adjuvant fluoropyrimidine-based treatment after primary tumour resection. However, additional prospective studies are mandatory to define the precise role of TS in adjuvant therapy.

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“…However, Edler and co-workers demonstrated that patients with high TS may benefit from adjuvant 5-FU-based therapy [38]. Several recent clinical studies have demonstrated that TS was not capable of predicting outcome to 5-FUbased treatment [39,40]. An intergroup combined analysis was carried out to assess the prognostic significance of TS expression in Stage II and III CRC and further evaluate the role of TS as a predictor of response to adjuvant 5-FU-based therapy.…”

Section: Thymidylate Synthasementioning

confidence: 99%

Have we Made Progress in Pharmacogenomics? the Implementation of Molecular Markers in Colon Cancer

Allen¹,

Johnston²

2005

Pharmacogenomics

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For the last 40 years, 5-fluorouracil (5-FU) has remained the treatment of choice in both the adjuvant and advanced treatment of colorectal cancer (CRC). However, 5-FU monotherapy produces response rates of only 10-20% in the advanced setting. 5-FU has been combined with newer agents, such as oxaliplatin and irinotecan, and this has significantly increased response rates to 40-50% in the advanced setting. More recently, novel biological agents, such as the monoclonal antibodies targeting either the epidermal growth factor receptor or vascular endothelial growth factor, have shown to provide additional clinical benefit for patients with metastatic CRC. A number of predictive markers have been identified for CRC to date. However, their usefulness as individual markers of response has led to somewhat inconclusive results. Therefore, there is a need to identify panels of predictive markers of response to therapy for advanced CRC, in order to improve these disappointing response rates. The advent of high-throughput methodologies, such as microarrays, enables tumor samples to be profiled on a global scale. This technology has been utilized to develop predictive markers for a wide range of tumor types to date, and hopefully this technology can be translated into the CRC setting with the hope of predicting the response of each individual tumor to chemotherapy.

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Thymidylate synthase and p53 expression do not predict chemotherapy outcome in metastatic colorectal carcinoma

Cited by 5 publications

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The prognostic significance of thymidylate synthase and dihydropyrimidine dehydrogenase in colorectal cancer of 303 patients adjuvantly treated with 5‐fluorouracil

The prognostic significance of thymidylate synthase and dihydropyrimidine dehydrogenase in colorectal cancer of 303 patients adjuvantly treated with 5‐fluorouracil

Thymidylate synthase expression and prognosis of patients with gastrointestinal cancers receiving adjuvant chemotherapy: a review

Have we Made Progress in Pharmacogenomics? the Implementation of Molecular Markers in Colon Cancer

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