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Thymidylate synthase expression and p21(WAF1)/p53 phenotype of colon cancers identify patients who may benefit from 5-fluorouracil based therapy.

Sulzyc-Bielicka V, Domagala P, Bielicki D, Safranow K, Domagala W - Cell Oncol (Dordr) (2013)

Bottom Line: Studies on the expression of thymidylate synthase (TS) in colorectal cancers (CRCs) have failed to provide unequivocal prognostic or predictive information.A cohort of 189 CRCs was asssessed for TS, p21(WAF1) and p53 expression on tissue microarrays using immunohistochemistry, and associations with disease-free survival (DFS) and overall survival (OS) of the patients were assessed using univariate and multivariate analyses.Therefore, we suggest that assessing TS expression in conjunction with p21(WAF1)/p53 immunophenotyping of colon cancers may improve the selection of patients suitable for 5FU-based adjuvant chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Pomeranian Medical University, Szczecin, Poland.

ABSTRACT

Background: Studies on the expression of thymidylate synthase (TS) in colorectal cancers (CRCs) have failed to provide unequivocal prognostic or predictive information. Here, we assessed the prognostic significance of TS expression in Astler-Coller stage B2 and C CRCs defined by a p21(WAF1)/p53 immunophenotype in patients subjected to 5-fluorouracil (5FU)-based adjuvant therapy.

Methods: A cohort of 189 CRCs was asssessed for TS, p21(WAF1) and p53 expression on tissue microarrays using immunohistochemistry, and associations with disease-free survival (DFS) and overall survival (OS) of the patients were assessed using univariate and multivariate analyses.

Results: TS expression led to the stratification of patients with colon cancer, but not rectal cancer, with immunophenotypes other than p21(WAF1)+/p53- (referred to as P&P) into subgroups characterized by a worse (P&P TS+) and a better (P&P TS-) DFS and OS, in univariate (P = 0.006 and P = 0.005, respectively) and multivariate (P = 0.0004 and P = 0.002, respectively) analyses. The p21(WAF1)+/p53- immunophenotype was associated with a favorable prognosis, irrespective of TS expression.

Conclusions: The strong association observed between the P&P TS+ immunophenotype and a worse DFS and OS suggests a predictive significance of TS expression for 5FU-based adjuvant therapy in patients with colon cancers exhibiting the P&P immunophenotype. In addition, our findings suggest that the appropriate target for assessment of TS expression as a prognostic/predictive marker is a subgroup of colon cancers with an immunophenotype other than p21(WAF1)+/p53-, and that only in this subgroup high TS expression is associated with an unfavorable DFS and OS. Therefore, we suggest that assessing TS expression in conjunction with p21(WAF1)/p53 immunophenotyping of colon cancers may improve the selection of patients suitable for 5FU-based adjuvant chemotherapy.

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Schematic algorithm for determining the prognostic significance of nuclear TS expression in patients with stage B2 + C colon cancer subjected to 5FU-based adjuvant chemotherapy
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Fig8: Schematic algorithm for determining the prognostic significance of nuclear TS expression in patients with stage B2 + C colon cancer subjected to 5FU-based adjuvant chemotherapy

Mentions: We conclude that (1) the p21WAF1+/p53- immunophenotype is associated with a favorable prognosis in patients with stage B2 + C colon cancer treated with 5FU-based chemotherapy, regardless of the level of TS expression, (2) TS expression stratifies patients with colon cancer exhibiting immunophenotypes other than p21WAF1+/p53- and treated with 5FU in two subgroups characterized by a worse (high TS expression) and a better (low TS expression) prognosis. The observed strong association of the P&P TS+ immunophenotype with a worse DFS in both univariate and multivariate analyses suggests the predictive significance of TS expression for 5FU-based adjuvant therapy in patients with colon cancer exhibiting the P&P immunophenotype. Finally, (3) the results of this study suggest that future clinical trials evaluating the predictive significance of TS expression in colon cancer for 5FU-based adjuvant chemotherapy should take the p21WAF1/p53 immunophenotype of the tumor cells into account. Therefore, we propose a summarizing algorithm (depicted in Fig. 8) as a starting point for clinical trials assessing the predictive significance of TS expression in patients with stage B2 + C colon cancer subjected to 5FU-based adjuvant chemotherapy. Since this is a retrospective study, our results should be confirmed in additional prospective randomized studies.Fig. 8


Thymidylate synthase expression and p21(WAF1)/p53 phenotype of colon cancers identify patients who may benefit from 5-fluorouracil based therapy.

Sulzyc-Bielicka V, Domagala P, Bielicki D, Safranow K, Domagala W - Cell Oncol (Dordr) (2013)

Schematic algorithm for determining the prognostic significance of nuclear TS expression in patients with stage B2 + C colon cancer subjected to 5FU-based adjuvant chemotherapy
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3921584&req=5

Fig8: Schematic algorithm for determining the prognostic significance of nuclear TS expression in patients with stage B2 + C colon cancer subjected to 5FU-based adjuvant chemotherapy
Mentions: We conclude that (1) the p21WAF1+/p53- immunophenotype is associated with a favorable prognosis in patients with stage B2 + C colon cancer treated with 5FU-based chemotherapy, regardless of the level of TS expression, (2) TS expression stratifies patients with colon cancer exhibiting immunophenotypes other than p21WAF1+/p53- and treated with 5FU in two subgroups characterized by a worse (high TS expression) and a better (low TS expression) prognosis. The observed strong association of the P&P TS+ immunophenotype with a worse DFS in both univariate and multivariate analyses suggests the predictive significance of TS expression for 5FU-based adjuvant therapy in patients with colon cancer exhibiting the P&P immunophenotype. Finally, (3) the results of this study suggest that future clinical trials evaluating the predictive significance of TS expression in colon cancer for 5FU-based adjuvant chemotherapy should take the p21WAF1/p53 immunophenotype of the tumor cells into account. Therefore, we propose a summarizing algorithm (depicted in Fig. 8) as a starting point for clinical trials assessing the predictive significance of TS expression in patients with stage B2 + C colon cancer subjected to 5FU-based adjuvant chemotherapy. Since this is a retrospective study, our results should be confirmed in additional prospective randomized studies.Fig. 8

Bottom Line: Studies on the expression of thymidylate synthase (TS) in colorectal cancers (CRCs) have failed to provide unequivocal prognostic or predictive information.A cohort of 189 CRCs was asssessed for TS, p21(WAF1) and p53 expression on tissue microarrays using immunohistochemistry, and associations with disease-free survival (DFS) and overall survival (OS) of the patients were assessed using univariate and multivariate analyses.Therefore, we suggest that assessing TS expression in conjunction with p21(WAF1)/p53 immunophenotyping of colon cancers may improve the selection of patients suitable for 5FU-based adjuvant chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Pomeranian Medical University, Szczecin, Poland.

ABSTRACT

Background: Studies on the expression of thymidylate synthase (TS) in colorectal cancers (CRCs) have failed to provide unequivocal prognostic or predictive information. Here, we assessed the prognostic significance of TS expression in Astler-Coller stage B2 and C CRCs defined by a p21(WAF1)/p53 immunophenotype in patients subjected to 5-fluorouracil (5FU)-based adjuvant therapy.

Methods: A cohort of 189 CRCs was asssessed for TS, p21(WAF1) and p53 expression on tissue microarrays using immunohistochemistry, and associations with disease-free survival (DFS) and overall survival (OS) of the patients were assessed using univariate and multivariate analyses.

Results: TS expression led to the stratification of patients with colon cancer, but not rectal cancer, with immunophenotypes other than p21(WAF1)+/p53- (referred to as P&P) into subgroups characterized by a worse (P&P TS+) and a better (P&P TS-) DFS and OS, in univariate (P = 0.006 and P = 0.005, respectively) and multivariate (P = 0.0004 and P = 0.002, respectively) analyses. The p21(WAF1)+/p53- immunophenotype was associated with a favorable prognosis, irrespective of TS expression.

Conclusions: The strong association observed between the P&P TS+ immunophenotype and a worse DFS and OS suggests a predictive significance of TS expression for 5FU-based adjuvant therapy in patients with colon cancers exhibiting the P&P immunophenotype. In addition, our findings suggest that the appropriate target for assessment of TS expression as a prognostic/predictive marker is a subgroup of colon cancers with an immunophenotype other than p21(WAF1)+/p53-, and that only in this subgroup high TS expression is associated with an unfavorable DFS and OS. Therefore, we suggest that assessing TS expression in conjunction with p21(WAF1)/p53 immunophenotyping of colon cancers may improve the selection of patients suitable for 5FU-based adjuvant chemotherapy.

Show MeSH
Related in: MedlinePlus