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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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Distribution of TS histoscores in the study group (n = 189)
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Fig3: Distribution of TS histoscores in the study group (n = 189)

Mentions: Immunohistochemical nuclear stainings were assessed using the anti-p53 (Fig. 1a and b), anti-TS (Fig. 1c) and anti-p21 (Fig. 1d) antibodies. High p53 (p53+) nuclear expression (histoscore p53 >7) was seen in 114 out of 189 samples (60.3 %). The distribution of the p53 histoscores is shown in Fig. 2. High TS (TS+) expression (histoscore TS ≥2) in tumor cell nuclei was noted in 127 out of 189 samples (67.2 %). The distribution of the TS histoscores is shown in Fig. 3. Nuclear expression of p21WAF1 (p21+) was noted in 126 out of 189 samples (66.7 %). The p21WAF1+/p53- immunophenotype was found in 50 out of 185 samples (26.5 %). Loss of MMR proteins was found in 31 out of 185 samples (16.8 %).Fig. 1


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)

Distribution of TS histoscores in the study group (n = 189)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Distribution of TS histoscores in the study group (n = 189)
Mentions: Immunohistochemical nuclear stainings were assessed using the anti-p53 (Fig. 1a and b), anti-TS (Fig. 1c) and anti-p21 (Fig. 1d) antibodies. High p53 (p53+) nuclear expression (histoscore p53 >7) was seen in 114 out of 189 samples (60.3 %). The distribution of the p53 histoscores is shown in Fig. 2. High TS (TS+) expression (histoscore TS ≥2) in tumor cell nuclei was noted in 127 out of 189 samples (67.2 %). The distribution of the TS histoscores is shown in Fig. 3. Nuclear expression of p21WAF1 (p21+) was noted in 126 out of 189 samples (66.7 %). The p21WAF1+/p53- immunophenotype was found in 50 out of 185 samples (26.5 %). Loss of MMR proteins was found in 31 out of 185 samples (16.8 %).Fig. 1

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